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Formulating Better Medicines for Children
Poster no.
Abstract tile Authors Contact details of presenting author
2 #2 Minimised tablet sizes: Technical feasibility compared to adult´s tablet formulations
Jessica Soto, Peter Kuehl, Arnaud Mauler, Gesine Winzenburg, and Sabine Desset-Brethes
3 #3 Development of a pediatric treatment against sickle cell disease crisis
Denis Larrouture, Gilles lemagnen, Pascal Millet, Steve Amoussou Guenou, Luc Grislain, and Pascale Gueroult
4 #4 Exploring the acceptability of paediatric microneedle-mediated monitoring among children
Karen Mooney, James C. Mcelnay, and Ryan F. Donnelly
5 #5 Influence of Aqueous Ethylcellulose Coating on the Performance of Hydrophilic Polyethylene Oxide Mini-Matrices Containing a Freely Water Soluble Drug
Kevin Hughes, Hue Vuong, Marina Levina, Tom Farrell, and Ali Rajabi-Siahboomi
6 #6 The Influence of Hydrophilic Pore Formers on Metoprolol Succinate Release from Mini-tabs Coated with Aqueous Ethylcellulose Dispersion
Kevin Hughes, Hue Vuong, Marina Levina, Tom Farrell, and Ali Rajabi-Siahboomi
7 #7 chewing-gums as paediatric oral dosage form to improve the local treatment of oral candidiasis
Rossella Dorati, Barbara Colzani, Ida Genta, Tiziana Modena, and Bice Conti
8 #8 The use of Eudragit E for coating of paediatric minitablets with candsartan cilexetil
Anna Kluk and Malgorzata Sznitowska
[email protected]; [email protected]
9 #9 Characteristics of disintegrants and viscosity increasing substances for use in ex tempore prepared “on a spoon” gels for administration of drugs in children
Eliza Wolska, Magdalena Boniecka, and Malgorzata Sznitowska
10 #10 stability study of the pediatric oral solutions with propranolol hydrochloride
Sylva Klovrzová, Zdenka Šklubalová, Lukáš Zahálka, Ludmila Matysová, and Petr Horák
11 #11 Development and Evaluation of Age Appropriate Pellet Formulations for an antiepileptic drug
Sonia Cabana Montenegro, Maria Begoña Delgado-Charro, and Nikoletta Fotaki
12 #12 Acceptance of and preference among four oral dosage forms in infants and pre-school children
Diana A. Van Riet-Nales, Barbara J. De Neef, Alfred F.A.M. Schobben, J. Ferreira, Toine C.G.
European Paediatric Formulation Initiative (EuPFi) The 4th Annual Conference of the EuPFI was held in Prague in September 2012. There were 69 abstracts (including oral
presentations poster presentations). The abstracts of those presentations are listed below.
Formulating Better Medicines for Children
Egberts, and Catharine M.A. Rademaker
13 #13 Delivery of aerosolised fluticasone propionate via valved holding chamber with facemask: Beware facemask leakage
Ritchie Sharpe, Mark Nagel, Valentina Avvakoumova, Heather Schneider, Rubina Ali, and Jolyon Mitchell
14 #14 Milk-based formulations: The evaluation of meloxicam gastric tolerability in rats.
Georgia Charkoftaki, Evangelos Balafas, Nikolas Kostomitsopoulos, Sofia Tseleni-Balafouta, and Panos Macheras
15 #15 Novel milk-based formulations of nsaids: stability and physicochemical characteristics.
Georgia Charkoftaki, George Voyiatzis, Athanasios Chrissanthopoulos, Spyros N. Yannopoulos, Dimitris Fatouros, and Panos Macheras
16 #16 comparison of two sodium phenylbutyrate granule formulations
Nathalie Guffon, Yves Kibleur, William Coppalu, C. Tissen, and Joerg Breitkreutz
17 #17 Does small intestinal surface area correlate to dose adjustment calculations used in paediatric populations?
Hannah Katharine Batchelor and John Marriott
18 #18 Targeted paediatric biopharmaceutics knowledge is essential in critical cases
Hannah Katharine Batchelor and John Marriott
19 #19 Dexamethasone soluble tablets for paediatric use
Zouaoui Bourezg, Morgan Vabre, Vincent Grek, and Hatem Fessi
20 #20 Lipid microparticles obtained by spray chilling for paediatric use
Zouaoui Bourezg and Hatem Fessi
21 #21 Prevention of vitamin D insufficiency in Switzerland: a never-ending story
Sebastiano Antonio Giovanni Lava, Giacomo Domenico Simonetti, and Mario Giovanni Bianchetti
22 #22 Development of a low price liquid oral vehicle for paediatric use
Said G.C. Fonseca, Cristiani C.G.O. Lopes, Jamille A. Felix, Marina G. Medeiros, Livia Aline A. Batista, and Helena Lutescia L. Coelho
Formulating Better Medicines for Children
23 #23 In vitro deposition testing of two commercial dry powder inhalers using physical mouth-throat models and simulated inhalation profiles
Antje Below, Deborah Bickmann, and Joerg Breitkreutz
24 #24 Excipient screening for individually dosing by the Solid Dosage Pen
Eva Julia Laukamp and Jörg Breitkreutz
25 #25 Evaluation of a novel Pharmaburst® based ODT formulation for weight-specific dosing of Amoxicillin in children
Praveen Saligram [email protected]
26 #26 Dissolution Evaluation of Actimask® 92M, a Novel, Aqueously-Processed Taste-Masked Acetaminophen
John Tillotson [email protected]
27 #27 Development of anti-tb oral formulations for children
Said G. Fonseca, Maria A. A. Josino, Livia Aline A. Batista, Marina G.C. Medeiros, Helena Lutescia L. Coelho, and Fernanda N. Raffin
28 #28 EU Pediatric Regulation: do children really benefit(1)?
L. Schrier, M. Holmes, A. Mui, J. Van Gerven, and A. Cohen
29 #29 EU Pediatric Regulation: do children really benefit(2)?
L. Schrier, A. Mui, M. Holmes, J. Van Gerven, and A. Cohen
30 #30 optimizing the taste-masked formulation of acetaminophen using sodium caseinate and lecithin by experimental design
Thanh Huong HOANG THI, Mohamed LEMDANI, and Marie-Pierre FLAMENT
31 #31 Development of Spherical formulation of candesartan cilexetil for children
Takahiro Endo, Masahiro Goto, Masato Takahashi, Hideki Nakajima, Yoichi Ishikawa, Hidefumi Nakamura, and Junichiro Fujimoto
32 #32 Medicines for Children in Japan - New approach to bitter medicines -
Masaaki Habara, Hidekazu Ikezaki, Maki Yoneko, Sayaka Murata, and Jun Kojima
33 #33 determining surfactant effect in residual oil inclusion during the development of taste masked microsphere processing method.
Peter Mbwiiri Ikamati, Yvonne Perrie, Roderick B. Walker, and Daniel J. Kirby
34 #34 the development of a flow through dissolution test method for the determination of flucloxacillin release properties of taste masked
Peter Mbwiiri Ikamati, Yvonne Perrie, Roderick B. Walker, and Daniel J. Kirby
Formulating Better Medicines for Children
microspheres
35 #35 the impact of the european paediatric regulation on authorised medicines for children – uk experience
Sarah K. Branch [email protected]
36 #36 A questionnaire on factors influencing clinical development of medicines for children in Japan
Maki Yoneko, Nao Tuschida, Nanako Nagafuchi, Tetsuharu Nagamoto, Michihiro Kitagawa, and Jun Kojima
[email protected]; [email protected]
38 #38 Considerations of children and parents to participate in a pediatric formulation trial
Lidwien Hanff, M. Cavazza, R. Pieters, and C. Zwaan
39 #39 Printing of personalized medicine for paediatric and geriatric use
Natalja Genina, Daniela Fors, Petri Ihalainen, Jouko Peltonen, and Niklas Sandler
40 #40 Taste Assessment of Methylxanthines using an Electronic Tongue
Xolani Dereck Gondongwe, Duncan Craig, Paul Flanders, David Wright, and Paul Grassby
41 #41 Electronic taste assessment of bilayer orodispersible films
Maren Preis, Katharina Schneider, Jennifer Kukawka, Jens Broscheit, Norbert Roewer, and Jörg Breitkreutz
42 #42 Introduction of a new disintegration test for orodispersible films
Maren Preis and Jörg Breitkreutz
43 #43 Melt granulation as a single-step manufacturing process of a taste masked dosage form containing a highly soluble API
Carolin Eckert, Miriam Pein, and Jörg Breitkreutz
44 #44 Development of a palatable midazolam formulation for paediatric use
Maren Preis, Jens Broscheit, Norbert Roewer, and Jörg Breitkreutz
45 #45 A new bilastine tablet: dispersible for paediatric use. Industrial scale-up and stability evaluation.
E. BEASCOA, L. GONZÁLEZ, C. PUMAR, I. ORTEGA, H. BLANCO, K. SUSTACHA, E. CORTA, A. GONZALO, and M.L. LUCERO
Formulating Better Medicines for Children
46 #46 Palatability study of a flavored low price liquid oral vehicle for pediatric use among children and parents
Marina Garruti Medeiros, Deborah Santos Garruti, Patrícia Pontes Thé, Said Cruz Fonseca, Maria Aparecida Josino, Solange Cecilia Dantas, Cristiani Lopes Oliveira, and Helena Luna Coelho
47 #47 Development of a pediatric formulation for a poorly soluble anti-HIV compound
Roger C. Embrechts, Urbain Delaet, Guy Smans, and Albertina Ariën
48 #48 Exposition of neonates to toxic pharmaceutical excipients in a NICU in Brasilia-Brazil, a followup study.
ALCIDESIO SALES SOUZA JR, SARA CORREA C. FIGUEIREDO, RAFAEL SOUZA SANTOS, DJANILSON BARBOSA SANTOS, and HELENA L. LUNA COELHO
49 #49 Characterization of commercially available oral dispersible films (odfs)
Ana Borges, Cláudia Silva, Jorge F.J. Coelho, and Sérgio Simões
50 #50 Fast disintegrating tablet formulation forming a viscous pulp easy to swallow
Stefanie Bold and Peter Gruber
51 #51 end-user perceptions, preferences and practices: piloting the ‘children’s acceptability of oral formulations’ (calf) medicines survey
Sejal Ranmal, Anne Cram, and Catherine Tuleu
52 #52 actively involving children and young people in research – lessons learnt from developing and pre-testing the calf survey questionnaires
Sejal Ranmal, Catherine Tuleu, and Jennifer Newman
53 #53 2nd Generation of Mini-Tablet Dosing Dispenser - a Simple and Affordable Solution
Rolf Eilers [email protected]
54 #54 Developing the New Type of Oral Dosage Form for Children: GT™(Gel Together)
Shuji Morimoto [email protected]
55 #55 Technology of the New Type of Oral Dosage Form for Children: Gel Together (GT™)
Shuji Morimoto [email protected]
56 #56 Age-Appropriate Evaluation and Availability of Enteral Drug Formulations Recommended in Essential Medicines List for Children
Jennifer C. Duncan, Samuel Orubu, Catherine Tuleu, Mark A. Turner, and Anthony J. Nunn
57 #57 amlodipine: exploring the methods to achieve a 2.5 mg dose.
Paul mccague, Caoimhe Quinn, Lesley-Ann
Formulating Better Medicines for Children
mccullough, James mcelnay, and Ryan Donnelly
58 #58 paediatric extemporaneous formulations: a service evaluation in the primary care setting
Paul mccague, James mcelnay, and Ryan Donnelly
59 #59 opinions & experiences of community and hospital pharmacists on extemporaneous preparation of medicines and specials.
Paul mccague, James mcelnay, and Ryan Donnelly
60 #60 Extemporaneous compounding in Nigeria - A pilot study of a children's unit in a tertiary hospital
Samuel Orubu, Chinyere Okwelogu, Tony Nunn, and Catherine Tuleu
61 #61 Oral priority medicines for children: Availability in the United Kingdom (U.K) and United States (U.S)
Samuel Orubu, Jennifer Duncan, Mark A. Turner, Tony Nunn, and Catherine Tuleu
62 #62 medicine flavour and formulation preference amongst school children in the west midlands region of the uk
Daniel Jon Kirby, Carly Tibbins, Claire Callens, and John Marriott
63 #63 Difficulties in administer medicines to children with chronic illnesses at home
Patrícia Quirino Costa, Marina Garruti Medeiros, Débora Silva Gonçalves, and Helena Luna Coelho
64 #64 The use of PILLGLIDE in children: a pilot study
Mamta Jagani, Hélène Legay, Sejal Ranmal, Kuan Ooi, and Catherine Tuleu
65 #65 paediatricians’ perspectives and practices using solid oral dosage forms for children
Sejal Ranmal, Anne Cram, and Catherine Tuleu
66 #66 drug characteristics influence on children compliance
Petkova Valentina [email protected]
67 #67 Developing novel cerates as substitutes for White Soft Paraffin
Joachim Köck [email protected]
Formulating Better Medicines for Children
2. MINIMISED TABLET SIZES: TECHNICAL
FEASIBILITY COMPARED TO ADULT´S
TABLET FORMULATIONS
Jessica Soto; Peter Kuehl; Arnaud Mauler;
Gesine Winzenburg; Sabine Desset-Brethes
Novartis Pharma AG, Technical Research &
Development
During the paediatric development it would
be a straightforward strategy to resume
adult´s tablet formulation and reduce the
tablet size for gaining an age appropriate
dosage form. However, the reduction of
tablet sizes below 5 mm down to 2 mm could
lead to new technical challenges. Based on
the data from adult´s formulation it is not
clear in how far granules and blends thereof
are suitable for smaller tablets and
minitablets. A significant impact on the
compactability and mass uniformity can be
expected for the tabletting process.
Studies at lab scale were performed to
investigate the compactability and flowability
of different compositions for 2 different drug
substances in dependence of the tablet size.
Multiple punch tools with 2,3,4 and 5 mm
round punches were used on a single punch
tabletting machine to assess the tablet
properties after compressing blends
manufactured with different drug loads, and
with different processes, i.e. dry blending,
roller compaction, or wet granulation.
Normalised compression profiles were
established for evaluating the impact of tablet
size on compactability. Flowability methods
have been applied, such as ring shear cell,
avalanche test, in order to predict the
suitability of a formulation for a tabletting
process.
Tabletting properties are improved for
reduced tablet sizes particularly for 2 mm. But
the compactability is deteriorated by the
application of granulation. Since granulation
becomes more important for ensuring
sufficient flowability during tabletting with
decreasing tablet sizes, this leads to
limitations in drug load, which might deviate
from the adult´s formulation.
References:
C. Tissen, K.Woertz, J.Breitkreutz,
P.Kleinebudde, 2011
Development of mini-tablets with 1 mm and
2 mm diameter
Int. J. Pharm. 416, Issue 1, pp. 164-170
P.Lennartz, J.B.Mielck, 1998. Minitabletting:
improving the compactability of paracetamol
powder mixtures. Int. J. Pharm.173, pp. 75-85.
3. DEVELOPMENT OF A PEDIATRIC
TREATMENT AGAINST SICKLE CELL
DISEASE CRISIS
D.Larrouture1, G.Lemagnen1, P. Millet2, S.
Amoussou Guenou1, L. Grislain1, P.Gueroult1
1Laboratoire de Technologie Pharmaceutique
Industrielle, 2EA 4575 Développements
Analytiques et Pharmaceutiques appliqués
aux Maladies Négligées et aux Contrefaçons,
Université Bordeaux Segalen, 146 rue Leo
Saignat, 33076 Bordeaux France
Tél : +33557571193, Fax : +33556960567,
email : [email protected]
Background:
Approximately 5% of the world’s population
carries trait genes for hemoglobin disorders,
mainly Sickle Cell Disease (SCD) and
thalassemia. Aspartame has been described
as an oral treatment, best efficiency with
6mg/kg dose [1]. As SCD crises begin between
12 and 18 months, the aim of this study is to
propose a child friendly treatment (preventive
and/or crisis) of the SCD.
Methods:
We propose the use of Phenylalanine
contained in Cajanus Cajan used in Benin and
Nigeria against crisis[2], previously identified
Formulating Better Medicines for Children
as the useful part (50%) of aspartame. To
confirm this choice, we performed an Emmel
test on SCD blood samples with neat
Phenylalanine[1].
The pediatric dosage form chosen was
soluble, flavoured (chocolate, coffee and
vanilla), sugar free granules. Phenylalanine
(40-150µm calibrated) and excipients (isomalt
and flavouring agent) were wet granulated;
the granules were then dried and calibrated
(range 300-800µm). API contents and
dissolution profiles were performed by UV
spectroscopy.
Findings:
Emmel test with phenylalanine: best results
(reduction and stability) were obtained with
the same dose than aspartame.
The optimal granules contained 18%
Phenylalanine, 81% isomalt (non cariogenic,
high digestive tolerance) and 1% chocolate
aroma
These granules (6mg of phenylalanine per
0.05ml of granules) were conformed to
pharmacopeial standards for immediate
release (more than 80% within 15 min)
Conclusions:
For an equivalent dose the in-vivo results with
phenylalanine (6mg/kg) should be at least
better than those obtained with aspartame
(80% reduction of sickled cells until 5.5 hours
with 6mg/kg [1]).
As upper Phenylalanine dose is 40mg/kg/day
(EFSA), this dosage form (easily processed) is a
nutrition product and may allow clinical tests
(contra indicated for children with
phenylketonuria), with few risks. We propose
two measuring spoons (STIPLASTICS 3mm
diameter 0.05ml spoons): 0.05ml and 0.5ml
allowing /kg and /10kg dosage, twice or three
times a day, depending on response.
References
[1] Aspartame effect in sickle cell anemia.
Manion CV, Howard J, Ogle B, Parkhurst J,
Edmundson A. Clin Pharmacol Ther. 2001
May;69(5):346-55.
[2] Phenylalanine is the predominant
antisickling agent in Cajanus cajan seed
extract. Ekeke GI, Shode FO. Planta Med. 1990
Feb;56(1):41-3.
4. EXPLORING THE ACCEPTABILITY OF
PAEDIATRIC MICRONEEDLE-
MEDIATED MONITORING AMONG
CHILDREN
Karen Mooney, James C. McElnay, Ryan F.
Donnelly
School of Pharmacy, Queen’s University
Belfast, 97 Lisburn Road, Belfast
Correspondence: [email protected]
Background
The potential use of microneedles (MN) in
children has recently been recognised1, in
particular due to fear of conventional
needles2. MN-mediated monitoring could
offer reduced pain, as well as a blood-free
alternative to blood sampling by instead
facilitating the collection of interstitial fluid.
The objectives of the present study was to
explore the views of children on the use of
MN patches as an alternative approach to
blood sampling in paediatric monitoring.
Methods
A qualitative approach was taken to facilitate
exploration of views on this unfamiliar topic3.
Following ethical approval, children were
recruited through local schools to participate
in focus groups discussions and informed
consent obtained from all participants and
their parent/guardian(s). Audio-recordings
were transcribed verbatim, before transfer to
QSR Nvivo® for thematic content analysis.
Findings
A total of 13 focus groups (n = 6-8) were
conducted with children aged 10-14 years.
The desire for an alternative technique to
blood sampling was compelling and largely
Formulating Better Medicines for Children
based on the opportunity for reduced pain
and trauma. Appearance represented a crucial
factor for acceptability among children. MN
patches seemed more visually acceptable,
aided by their small size and low penetration
depths. Accuracy of sampling volume and
allergy potential were raised as concerns.
Discussion
This work provides an initial indication of MN
acceptability among children as an alternative
monitoring technique and highlights factors
considered important by children regarding
techniques to be used on them. Such insights
are likely to be critical in the development of
this approach, as well as for other age-
appropriate techniques.
References
1. Birchall, J., Clemo, R., Anstey, A. & John, D.
2011, "Microneedles in Clinical Practice-An
Exploratory Study Into the Opinions of
Healthcare Professionals and the Public",
Pharmaceutical research, vol. 28, no. 1, pp.
95-106.
2. Rice, L. 1993, "Needle phobia - An
anesthesiologist's perspective", The Journal of
Pediatrics, vol. 122, no. 5, pp. S9-S13.
3. Curry, L., Nembhard, I. & Bradley, E. 2009,
"Qualitative and Mixed Methods Provide
Unique Contributions to Outcomes Research",
Circulation, vol. 119, no. 10, pp. 1442-1452.
5. INFLUENCE OF AQUEOUS
ETHYLCELLULOSE COATING ON THE
PERFORMANCE OF HYDROPHILIC
POLYETHYLENE OXIDE MINI-
MATRICES CONTAINING A FREELY
WATER SOLUBLE DRUG
Kevin Hughes, Hue Vuong, Marina Levina,
Tom Farrell, and Ali Rajabi-Siahboomi
Colorcon, UK
Background and Objectives:
The majority of oral extended release (ER)
drug delivery dosage forms are matrix-based
systems that rely on fast formation of a
progressive hydrated gel layer in the presence
of fluids, these are not applicable to most
paediatric age groups. A mini-matrix
formulation provides the benefits of a matrix
and a Multi-Particulate (MP). The aims of this
study are to investigate the effect of aqueous
Ethyl Cellulose (EC) coating on performance of
PEO ER mini-matrices containing a freely
water-soluble (157 mg/mL) drug, metoprolol
succinate.
Methods:
Metoprolol succinate mini-tablets are seal-
coated with a 20% w/w aqueous solution of
Opadry® II Clear film coating followed by EC
dispersion (Surelease, Colorcon) in a fluid-bed
coater. Dissolution tests were conducted
using USP II apparatus at 50 rpm in 500 mL of
pH 6.8 phosphate buffer.
Findings
Uncoated and seal-coated PEO mini-matrices
released drug within 3 hours. Slower drug
dissolution was obtained for higher coating
weight gain (WG) of Surelease. For 12-hour
and longer release at least 12% coating WG
was required. Hydrated ER coated mini-
matrices ruptured around tablet edges during
dissolution testing. For lower coating levels,
this occurred much earlier as compared to
samples with 12-20% WG of Surelease.
Discussion
Release of freely water-soluble metoprolol
succinate from uncoated and seal-coated
mini-matrices occurred within 3 hours, further
control of release can be achieved by applying
an EC coating. This study demonstrates the
level of control possible on in-vitro drug
release form a dosage form that is applicable
to several paediatric age groups.
6. THE INFLUENCE OF HYDROPHILIC
PORE FORMERS ON METOPROLOL
SUCCINATE RELEASE FROM MINI-
Formulating Better Medicines for Children
TABS COATED WITH AQUEOUS
ETHYLCELLULOSE DISPERSION
Kevin Hughes, Hue Vuong, Marina
Levina, Tom Farrell, and Ali Rajabi-
Siahboomi
Background and Objectives:
Multiparticulate (MP) modified release (MR)
drug delivery systems provide a more reliable
in vivo dissolution performance when
compared to a single unit dosage form. Mini-
tabs combine the advantages of MP and have
excellent size characteristics that offer an
ideal substrate to coat with MR polymers.
Ethylcellulose (EC) is widely used in organic
and aqueous coating applications to achieve
extended release (ER) of drugs. This study
investigates the influence of pore-formers in
an aqueous EC system (Surelease) on the
release of a freely water-soluble drug from
coated mini-tabs.
Methods:
Metoprolol succinate mini-tablets are seal-
coated with a 20% w/w aqueous solution of
Opadry® II Clear film coating to 5% weight
gain (WG), followed by a 15% w/w aqueous
EC system with pore-former (same Opadry II
Clear) at two different ratios up to 16% WG.
Drug release rate from mini-tabs coated with
ethylcellulose coating was modulated by
varying the amount of hydrophilic pore
former and/or the level of film coating
applied.
Findings
Uncoated and seal-coated PEO mini-matrices
released drug within 3 hours. Application of
Surelease film resulted in a slower dissolution
rate. At least 12% WG of ER coating was
required to achieve a 12hr release profile. 18
and 20% Surelease WG resulted in nearly
zero-order drug release.
Discussion
Mini-tabs offer a reliable alternative to
conventional MP systems from which drug
release is effectively modulated. Mini-tablets
offer a high dose solid oral dosage form that
may be more acceptable to the paediatric
population than a single tablet.
7. CHEWING-GUMS AS PAEDIATRIC
ORAL DOSAGE FORM TO IMPROVE
THE LOCAL TREATMENT OF ORAL
CANDIDIASIS
R. Dorati, B. Colzani, , I. Genta, T. Modena, B.
Conti
Dept. Drug Sciences, University of Pavia, V.le
Taramelli, 12, 27100 Pavia (Italy),
E-mail: [email protected]
Purpose. To prepare chewing gums containing
antifungal drugs loaded microparticles for the
local treatment of oral candidiasis in
paediatric patients, improving children
compliance and drug bioavailability
Methods. Miconazole as model drug was
formulated into double-wall microparticles
with alginate core and chitosan wall. The
microaprticles were prepared by a vibration
nozzle technique based instrument
(Encapsulator B-395 pro, Büchi) equipped
with concentric nozzles. They were
characterized for process yield, particles size
(dynamic light scattering), chitosan coating
capacity (UV-VIS, GPC), drug encapsulation
efficiency and in vitro release (HPLC).
Moreover, the rehydration behaviour of
freeze dried microparticles was evaluated.
The in vitro release of the microparticles
incorporated into chewing gums was
evaluated.
Results. Satisfactory results were obtained in
terms of microparticles size (<200µm) and
process yields (about 80%), drug
microencapsulation efficiency >90% ) and
drug release (>45% in 15 minutes). Moreover,
considering miconazole poor water solubility
(360mg/ml ) and its affinity with gum matrix,
its loading into alginate/chitosan
Formulating Better Medicines for Children
microparticles improved its release rate from
the chewing gums. About 92% of loaded
microparticles were released undamaged
from the chewing gum matrix after 10
minutes test in artificial saliva. Chitosan layer
improved rehydration behaviour of freeze
dried microparticles with respect to uncoated
ones.
Conclusions. Miconazole loading into double-
wall chitosan/alginate microparticles and its
incorporation into chewing gums is useful to
improve drug release profile respect to
conventional formulations where the
antifungal molecules are dissolved in the gum
matrix. This medicated chewing gums
represent an innovative formulation useful to
improve the compliance in paediatric
patients.
8. THE USE OF EUDRAGIT E FOR
COATING OF PAEDIATRIC
MINITABLETS WITH CANDESARTAN
CILEXETIL
Anna Kluk, Małgorzata Sznitowska
Department of Pharmaceutical Technology,
Medical University of Gdańsk, Poland
[email protected], [email protected]
Background:
Minitablets (tablet diameter 2-3 mm) have
been described as a novel oral solid
multicompartment paediatric formulation [1].
It is important to design an appropriate
coating to mask unpleasant taste or protect
minitablets from fast desintegration in the
oral cavity, without significant influence on
drug release. To facilitate oral administration,
minitablets can be mixed with universal
dispersing medium in the form of a semisolid
oral gel. Such gel may be proposed in
different taste versions. This preliminary
studies have been undertaken to estimate
application properties of Eudragit E PO
coating for pediatric minitablets with
candesartan cilexetil intended for oral
application with carmellose sodium oral gel.
Methods:
Minitablets (2.5 and 3 mm) containing
candesartan (7% w/w) or placebo minitablets
were obtained by wet granulation method
and compressed using rotary tabletting
machine (Korsch XL 100, Germany) equipped
with spherical minipunches. The particles
were coated with Eudragit E PO dispersion
using laboratory coating equipment (InnoJet
AirCoater 025, Germany) to get 100 μm film
thickness. Placebo minitablets were evaluated
for desintegration time in dynamic and static
models
(PharmaTest, Germany and stereoscopic
microscope OptaTech X 2000, Poland).
Desintegration process was observed in acid
environment (0.1 mol/l HCl) and in pH 6.5.
The dissolution tests (Erweka DT 800
apparatus , Germany) for coated and
uncoated candesartan minitablets were
performed.
Results:
Obtained results showed that desintegration
time of coated placebo minitablets was
influenced by pH and also depended on the
chosen experimental method. In oral gel (pH
6.5) minitablets have disintegrated
considerably longer (40 min or 81 min,
depending on the experimental model) in
comparison to acid environment (2,8 min or
11 min, respectively). This process has almost
always started with film cracking on the edge
of the tablet, which was observed after 30
min in pH 6.5 and after less than 3 min in HCl.
Results of the dissolution tests have not
indicated statistic difference in candesartan
release profiles for coated and uncoated
minitablets.
Conclusion:
Formulating Better Medicines for Children
Eudragit E coating, 100 μm in thickness, is
sufficient to protect minitablets from quick
desintegration in pH of oral cavity or in the gel
(pH 6.5) proposed for suspending minitablets
before administration. On the other hand,
desintegration release of candesartan occurs
in the acid environment, which allows to
predict fast dissolution in vivo.
References:
1. S.A. Thomson, C. Tuleu, I. C. K. Wong, S.
Keady, K. G. Pitt i in.: Minitablets: New
modality to deliver
medicines to preschool-aged children,
Pediatrics 2009;123;e235-e238
9. CHARACTERISTICS OF
DISINTEGRANTS AND VISCOSITY
INCREASING SUBSTANCES FOR USE
IN EX TEMPORE PREPARED “ON A
SPOON” GELS FOR ADMINISTRATION
OF DRUGS IN CHILDREN
Eliza Wolska, Magdalena Boniecka,
Małgorzata Sznitowska
Department of Pharmaceutical Technology,
Medical University of Gdańsk,
80-416 Gdańsk, Hallera 107, Poland,
Background
Ex tempore hydrated powders gain recently
much interest as pediatric formulations
suitable for drugs unstable in aqueous
environment, such as antibiotics [1]. A
therapeutic dose of the powder can be placed
on a spoon and upon hydration with several
drops of water viscous gel is obtain. Similar
effect can be achieved by placing on a spoon
fast-disintegrating tablet. The texture of the
gel allows easier swallowing of the
preparation.
The aim of the present study was to evaluate
different gelling agents, alone or together
with superdisintegrants, as excipients suitable
for preparing powders fast hydrating on a
spoon, to be easily swallowed.
Methods
Disintegrants and viscosity increasing
substances (Tab. 1) alone and in mixture with
lactose (1:1) were investigated in respect of
their wettability as well as homogeneity after
hydrating with small amount of water (200 mg
of the powder and 1 ml of water), without
mixing. In the same manner powders
composed of disintegrant, lactose and guar
gum (1:1:1) were also studied.
Tab. 1. The investigated disintegrants and
gelling agents
Disintegrants
Viscosity
increasing
substances
Ac-Di-Sol
Gelcarin
GP379
Aerosil 200
Gelcarin
GP812
Blanose Guar
Emcosoy STS IP Klucel HF
F-MELT Type C and M
Metolose
60SH- 4000
Kelacid NF
Protanal
LF10/60FT
Kyron T-314
Protanal
LF10/60LS
LAB 4029 Xanthan gum
L-HPC LH-22
Lycatab C
Neusilin US2
Pearlitol Flash-Mannitol
Pharmaburst 500
Polyplasdone Ultra and XL
Polyvinylpyrrolidone K30
Prosolv Easy tab SP
Prosolv SMCC 50 and 90
RxCipients FM1000
Starch 1500
Vivastar P Type A
Formulating Better Medicines for Children
In order to further characterize the hydrated
powders the rheological properties as flow
curve and viscosity curve were analyzed using
Haake VT 550 Viscotester. The changes in
viscosity and swelling effect (Texture analyzer
TA.XT plus, Texture technologies, USA) were
analyzed in relation to the hydration time (2
min). The tests were also repeated using the
powder mixtures obtained in a lyophilization
process.
Results
Addition of lactose facilitated wettability and
dispersibility of some disintegrants. Guar gum
was chosen as the most advantageous
viscosity increasing substance. Depending on
the type of disintegrants, the viscosity of the
prepared gels ranged from 150 to 450 Pa·s.
Texture analyzer is suitable for distinguishing
between swelling behavior of the
preparations in a narrow viscosity range.
Ability to form a gel after freeze-drying
depended on the concentration of the
substance in the primary solution and,
consequently, the porosity of the matrix.
Conclusion
The best preparation was composed of guar
gum, lactose and F-Melt. Lyophilization has
not improved the functional properties of the
powders. Proposed formulation can be easily
reconstituted with small amount of water,
without stirring rapidly forming gel which can
be easily swallowed by a child. Such
formulations are designed to be administered
to children, but they can also be administered
to adults.
References
[1] R.G. Strickley, Q. Iwata, S. Wu, T.C. Dahl,
Pediatric drugs - a review of commercially
available oral formulations, J Pharm Sci 97(5)
(2008) 1731-1774
10. STABILITY STUDY OF THE PEDIATRIC
ORAL SOLUTIONS WITH
PROPRANOLOL HYDROCHLORIDE
Sylva Klovrzová1, Zdenka Šklubalová2, Lukáš
Zahálka3, Ludmila Matysová3, Petr Horák1
1 Hospital Pharmacy, University Hospital
Motol, Prague, Czech Republic
2 Department of Pharmaceutical Technology,
Charles University in Prague, Faculty of
Pharmacy, Hradec Králové, Czech Republic
3 Department of Analytical Chemistry, Charles
University in Prague, Faculty of Pharmacy,
Hradec Králové, Czech Republic
Objective. The aim of this work was to
formulate an extemporaneous paediatric oral
solution of propranolol hydrochloride (PROCL)
2 mg/mL for therapy of infantile
haemangioma or hypertension in the target
age groups of newborns to school children
and to evaluate its stability.
Methods. The citric acid solution and/or the
citrate-phosphate buffer solution,
respectively, were used as the vehicles to
achieve pH value of about 3, optimal for
stability of PROCL. Sugar syrup and/or sodium
saccharin 0.05 % w/v, alternatively, were used
as sweeteners to mask the bitter taste of
PROCL. All solutions were stored in tightly
closed brown glass bottles at 2 - 8°C and/or 20
– 25°C, respectively. At time intervals 0 – 90
days, pH value and the content of PROCL and
sodium benzoate, if the preservative was used
in a preparation, were estimated using HPLC.
Results. All preparations were stable at both
storage temperatures with pH values in the
range of 2.8 – 3.2. The concentration of
PROCL and sodium benzoate varied within a
range of 97.5 – 103.2 % and/or of 96.4 – 103.0
%, respectively, at both temperatures used.
Conclusions. Based on the experimental
results, used vehicles were suitable to achieve
Formulating Better Medicines for Children
stability of PROCL solutions at both
temperatures of storage for 90 days. The
preparations formulated with the citrate-
phosphate buffer had better palatability than
those formulated with the citric acid solution.
The efficacy of sodium benzoate 0,05 % w/v in
the preserved preparations was proved
(Ph.Eur., 5.1.3).
Acknowledgements
This work was supported by the project of
Ministry of Health the Czech Republic for
conceptual development of research
organization 00064203 (University Hospital
Motol, Prague, Czech Republic) and Student
grant SVV-2012265 002.
11. DEVELOPMENT AND EVALUATION OF
AGE APPROPRIATE PELLET
FORMULATIONS FOR AN
ANTIEPILEPTIC DRUG
Sonia Cabana Montenegro, M. Begoña
Delgado-Charro, Nikoletta Fotaki*
Department of Pharmacy and Pharmacology,
University of Bath, Bath, UK
Background: Oral drug dosing to paediatric
patients is challenging1.2. Therapeutic and
technical advantages of pellets as
formulations of choice for paediatric patients
include convenient and reliable
administration, customized age dependent
dosing, low variability in gastrointestinal
absorption and ease of production. The
objective of this study was to develop and
evaluate pellet formulations for an
antiepileptic drug (carbamazepine) for their
potential for paediatric drug delivery.
Methods: Carbamazepine pellets with
microcrystalline cellulose and lactose were
produced via extrusion-spheronisation; the
spheronization time, water and drug content
were selected as critical variables. Pellets
were characterized macro- and micro-
scopically (SEM) including size distribution.
Carbamazepine’s release from pellets was
evaluated in water with 1% SLS and in
maleate buffer with physiological relevant
amount of surfactant (pH 6.5; blank FaSSIF
V23 with 0.1 % SLS) [900ml, USP apparatus I,
30rpm, 37°C] and compared to a marketed
carbamazepine IR formulatio
Carbamazepine was quantified via UV
spectroscopy at 286nm.
Findings: Pellets with appropriate physical
and size characteristics were produced.
Carbamazepine was not completely dissolved
from the marketed formulation in all the
conditions tested. Release of carbamazepine
from the pellets was higher than from the
marketed formulation. Water and drug
content were identified as the critical
variables whereas the spheronization time did
not have a significant effect. Interestingly, a
good release performance was observed for
the pellets formulation in the media
containing a physiologically relevant amount
of surfactant; while this was not observed for
the marketed formulation.
Discussion: Reliable carbamazepine pellets
have been prepared as a flexible paediatric
formulation.
References
1. Ernest TB, Elder DP, Martini
LG et al. Developing
paediatric medicines:
identifying the needs and
recognizing the challenges. J
Pharm Pharmacol 2007, 59(8),
1043-1055.
2. Breitkreutz J, Boos J.
Paediatric and geriatric drug
delivery. Expert Opin Drug
Deliv 2007, 4(1), 37-45.
3. Jantratid E, Janssen N, Reppas
C, Dressman JB. Dissolution
media simulating conditions
in the proximal human
gastrointestinal tract: an
Formulating Better Medicines for Children
update. Pharm Res. 2008,
25(7), 1663-76.
12. ACCEPTANCE OF AND PREFERENCE
AMONG FOUR ORAL DOSAGE FORMS
IN INFANTS AND PRESCHOOL
CHILDREN
Diana A. van Riet – Nales 1,2,3, J.C. de Neef 4,
Alfred F.A.M. Schobben2, José A. Ferreira 3,
Toine C.G. Egberts PharmD 2,5, Carin M.A.
Rademaker 5
1 Medicines Evaluation Board in the
Netherlands, Utrecht, The Netherlands
2 Utrecht University, Faculty of Science,
Utrecht Institute for Pharmaceutical Sciences
(UIPS), Department of Pharmacoepidemiology
and Clinical Pharmacology, Utrecht, The
Netherlands
3 National Institute for Public Health and the
Environment, Bilthoven, The Netherlands
4 Stichting Thuiszorg en Maatschappelijk
Werk Rivierenland, Tiel, The Netherlands
5 University Medical Centre Utrecht,
Department of Clinical Pharmacy, Utrecht,
The Netherlands
Correspondence: Diana A. van Riet – Nales,
PharmD Medicines Evaluation Board
Department of Chemical Pharmaceutical
Assessments (CFB), Graadt van Roggenweg .
E-mail: [email protected]
Company phone: +31 88 224 8217, Company
mobile: + 31 6 527 56 462
Background and aims
For decades, liquid formulations have been
considered as the favourable oral dosage form
in which to administer medicines to young
children. However, liquid medicines may have
disadvantages such as a bad taste or
restricted storage conditions. These
disadvantages may be overcome by the use of
oral solid flexible dosage forms such as
powders or mini-tablets. Therefore, the aim of
this study was to investigate the acceptance
of and preference among four oral dosage
forms in children aged 1-4 years in the
Netherlands.
Methods
Parents administered 4 placebo formulations
at home to their healthy child twice on one
day following a randomized cross-over design:
4-mm mini-tablet, powder, suspension and
syrup. Parents were asked to report the
child’s acceptance by a score on a 10-cm
visual analogue scale (VAS-score) and by the
result of the intake. At the end of the study
parents were asked to report the child and
parent preference.
Results
183 children were included and 151 children
were evaluated. The mini-tablet was
significantly better accepted than the other
forms (tablet/powder: p<0.001;
tablet/suspension: p<0.001; tablet/syrup:
p=0.0012). The data revealed a period or
cross-over effect indicating better acceptance
of dosage form taken first. The mini-tablet,
powder, suspension and syrup were fully
swallowed in 97%, 81%,
86% resp. 83% of all cases. Children and
parents preferred the tablet and syrup over
the suspension and the suspension over the
powder (all p<0.05).
Conclusions
All dosage forms were well accepted, but the
mini-tablets were the best accepted and
preferred dosage form.
13. DELIVERY OF AEROSOLISED
FLUTICASONE PROPIONATE VIA
VALVED HOLDING CHAMBER WITH
FACEMASK: BEWARE FACEMASK
LEAKAGE
Sharpe, R., Nagel, M.W., Avvakoumova, V.,
Schneider, H., Ali, R. and Mitchell, J.P.
Formulating Better Medicines for Children
Corresponding and presenting author: Ritchie
Sharpe, [email protected] , Trudell
Medical (Europe), Nottingham, UK
Background & Objectives: Leakage between
facemask-and-face may result in medication
loss to infants by valved holding chamber
(VHC)-facemask (1). Our laboratory study
evaluated how an inspiratory flow indicator
(IFI) can be used to avoid leakage.
Methods: An infant face with realistic soft-
tissue modeling (ADAM-III, Trudell Medical
International (TMI), London, Canada (2)) was
used to evaluate delivery of fluticasone
propionate (FP; 50 μg/actuation, GSK
(Canada)) via anti-static AeroChamber Plus®
VHC with Flow-Vu® IFI/infant mask (AC-Plus,
TMI) or OptiChamber® Diamond®
VHC/LiteTouch® small-mask (OD, Philips-
Respironics, Parsipanny, NJ, USA) (n=5
devices/group), simulating infant tidal-
breathing (tidal volume=155-mL, duty
cycle=33%, rate= 25-breaths/min. Each
facemask was applied to the face with the
same clinically-appropriate force (1.6 kg). The
IFI of the AC-plus was observed to be moving.
FP was recovered from the nasopharynx and
base (lung dose) of the model, and delivered
mass (DMFP) quantified by HPLC-
spectrophotometry as % label claim (LC).
Findings: DMFP (mean±S.D.) was significantly
greater from the AC-plus (25.8±5.3%) than the
OD (17.0±3.7%)(unpaired t-test, p=0.019). FP
collected on the facemask of the AC-plus
(6.2±1.9% LC), was slightly smaller than that
determined with the OD facemask (9.9±2.6%)
Discussion/Conclusion: Facemask-to-face
leakage was eliminated with the AC-plus, by
observing IFI movement. However, inasmuch
as the OD does not have an IFI, it was not
possible to do more than ensure that its
facemask was applied with the same force to
the model. Decreased aerosol delivery from
the OD is explainable in terms of leakage
between facemask and face, supported by
higher deposition in its facemask.
References:
1. Esposito-Festen JE, Ates B, Van Vliet
FLM, Verbraak AFM, de Jongste JC, and
Tiddens HAWM: Effect of a facemask leak on
aerosol delivery from a pMDI-spacer system. J
Aerosol Med. 2004;17:1–6.
2. Mitchell JP, Finlay JB, Nuttall JM,
Limbrick M, Nagel MW, Avvakoumova VI,
MacKay HA, Ali RS, and Doyle CC: Validation of
a new model infant face with nasopharynx for
the testing of valved holding chambers with
facemask as a patient interface. Respiratory
Drug Delivery 2010. Davis Healthcare
International Publishing LLC, River Grove, IL;
pp. 777–780, 2010.
14. MILK-BASED FORMULATIONS: THE
EVALUATION OF MELOXICAM
GASTRIC TOLERABILITY IN RATS.
G. Charkoftaki1*, E.G. Balafas2, N.G.
Kostomitsopoulos2, S. Tseleni-Balafouta3, P.
Macheras1
1Faculty of Pharmacy, National and
Kapodistrian University of Athens.
2Center of Experimental Surgery, Biomedical
Research Foundation of the Academy of
Athens.
3Medical School, National and Kapodistrian
University of Athens.
Background and Objectives: To study gastric
ulceration of a meloxicam milk-based
formulation in comparison to a commercial
tablet (Movatec®), in male Wistar albino rats.
Methods: Animals were administered with
drug per os once daily using gastric intubation
(gavage) for 7 days. Control groups (n=10)
received: I) 3.5% fat UHT milk, II) 1% sodium
carboxymethylcellulose in water, III) 10%
glycine buffer solution (0.05M, pH 12) in milk.
Test groups received a low (2mg/kg) and a
Formulating Better Medicines for Children
high dose (4mg/kg) of: A) meloxicam (~10 μm)
in medium I or II, B) commercial tablet of
meloxicam (Movatec®) crushed (~70 μm) in
medium I or II and C) meloxicam dissolved in
glycine buffer, dispersed in milk (the in house
developed milk-based formulation). On day 8
animals were sacrificed. Stomach contents
were collected for pH measurement, mucosal
surface was examined for erosions and
ulcerations under dissection microscope
(x100); histological analysis with
hematoxylin/eosin staining was performed.
Findings: For both doses administered, rats
that received meloxicam in solid formulation
(medium I) showed increased ulcer index
compared to the group that received the in
house developed formulation (meloxicam in
dissolved form). For pure drug, mean ulcer
value was 1.27±0.27, for the commercial
tablet was 1.9±0.2, while for the milk-based
formulation was 0.72±0.1; up to 2.7 times
decreased ulceration (4mg/kg). Macroscopic
findings were histologically confirmed:
neutrophils, vascular congestions and loss of
the superficial epithelium were detected.
Discussion: The in house developed milk-
based formulation, which presents meloxicam
in a dissolved form in the final solution,
showed decreased ulceration compared to
the two solid formulations of meloxicam.
15. NOVEL MILK-BASED FORMULATIONS
OF NSAIDS: STABILITY AND
PHYSICOCHEMICAL
CHARACTERISTICS.
Georgia Charkoftaki1*,George Voyiatzis2,
Athanasios Chrissanthopoulos3, Spyros N
Yannopoulos3, Dimitris Fatouros4,5, Panos
Macheras1 1Laboratory of Biopharmaceutics-
Pharmacokinetics, Faculty of Pharmacy,
University
of Athens, Panepistimiopolis 157 71, Athens,
Greece.
2FORTH ICEHT, Institute of Chemical
Engineering& High Temp Chemical
Procedures, GR-26504 Patras, Greece. 3Department of Materials Science, University
of Patras, GR-26504 Patras, Greece 4School of Pharmacy and Biomedical Sciences,
University of Portsmouth, St Michael’s
Building, White Swan Road, Portsmouth PO1
2DT, UK. 5Current address: Aristotle University of
Thessaloniki, School of Pharmacy, Department
of Pharmaceutical Technology, GR-54124
Thessaloniki, Greece.
Background and Objectives: Milk-based
formulations were prepared in situ by adding
alkaline-drug solutions into milk, containing
an array of drugs namely; ketoprofen,
tolfenamic acid, meloxicam, tenoxicam,
nimesulide and mefenamic acid. The purpose
of this work was to explore any possible
changes to the colloidal stability and to the
particle size of milk's components after the
addition of the alkaline drug-containing
solutions.
Methods: The physicochemical
characterization of the milk-based
formulations was performed by measuring
critical properties of the drug-milk system
such as the ζ-potential and the size
distribution of the emulsion components by
means of dynamic light scattering (DLS)
techniques. Raman spectroscopy studies of
freeze dried meloxicam/milk samples were
performed, in order to explore the
intermolecular interactions between
meloxicam and milk constituents.
Computational studies using Hartree-Fock
(HF) molecular orbital calculations were
carried out to determine the equilibrium
structure and the harmonic vibrational
frequencies of the neutral and ionic form of
the meloxicam molecule. Long term and
Formulating Better Medicines for Children
accelerated stability studies of the drug-
containing alkaline solutions were performed.
Findings: Alterations to the particle size of the
milk droplets in the presence of the different
drugs are rather case specific, as well as the ζ-
potential data unequivocally pointing to the
colloidal stability of these emulsions which is
prerequisite for a stable formulation. Raman
spectroscopy studies revealed interactions of
the drugs and the milk at the intermolecular
level. The drug-containing alkaline emulsions
exhibited remarkable stability over a period of
up to 12 months.
Discussion: These initial studies demonstrate
that milk possesses the stability required to
be used as a drug delivery system.
16. COMPARISON OF TWO SODIUM
PHENYLBUTYRATE GRANULE
FORMULATIONS
Guffon N1, M.D., Kibleur Y2, M.D., Pickup E3,
Coppalu W3, M.D., Tissen C, Ph. D.4,
Breitkreutz J4, M.D.
1 Hôpital Femme – Mère – Enfant, Centre de
Référence des maladies héréditaires du
métabolisme, 59 boulevard Pinel, 69577 Bron
Cedex, France
2 Lucane Pharma, 172 rue de Charonne 75011
PARIS Cedex, France
3 PAREXEL International London
4 Institute of Pharmaceutics and
Biopharmaceutics, Heinrich-Heine-University
Düsseldorf, Universitätsstraße 1, 40225
Düsseldorf, Germany
Background: Sodium phenylbutyrate (NaPB),
a treatment for urea cycle disorders, has an
extremely unpleasant, bitter taste which can
compromise compliance and metabolic
control.
Objectives: A new, taste-masked, coated-
granule formulation (Pheburane) is under
development and the taste characteristics,
dissolution and bioequivalence, including
taste, safety and tolerability, of this form was
compared to the available, licensed granule
product.
Results: The in vitro taste profile of NaPB
indicated a highly stimulant molecule.
Pheburane released NaPB only after a lag-
time of ~10s followed by a very slow release
during several minutes compared with
complete, immediate release of NaPB from
licensed granules. Pharmacokinetic evaluation
demonstrated bioequivalence of a 5g dose of
both products in 13 healthy volunteers. No
statistical difference was observed for
maximal plasma concentration (Cmax) or area
under the plasma concentration-time (AUC).
Confidence intervals for Cmax and AUC0-
were between 0.80 - 1.25. Both products
were well-tolerated. Pheburane was
significantly more acceptable, less bitter and
less salty (p<0.01).
Conclusion: These in vitro and in vivo taste
profiles indicate that Pheburane granules can
be swallowed before stimulation of taste
receptors by NaPB. Moreover Pheburane
granules are bioequivalent to the licensed
product. The availability of Pheburane should
improve compliance and efficacy of NaPB
treatment.
17. DOES SMALL INTESTINAL SURFACE
AREA CORRELATE TO DOSE
ADJUSTMENT CALCULATIONS USED
IN PAEDIATRIC POPULATIONS?
Dr Hannah Batchelor, Prof John Marriott
School of Clinical and Experimental Medicine,
College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, B15
2TT, UK
Background & Objectives: Paediatric dose
adjustments are traditionally made based on
simple measurements. Drug absorption
primarily occurs within the small intestine (SI)
Formulating Better Medicines for Children
therefore a comparison of the total surface
area of this site versus age is useful as a
physiologically relevant measure for dose
adjustment.
Methods: Yu (1999) calculated the surface
area of the SI in adults based on a radius of
1.5cm and a total length of 350cm. A single
source of SI lengths was used to enable direct
comparison across age ranges (Valentin 2002).
Table 1. Comparison of
physiological/anatomical parameters by age
category
Table 1. Comparison of
physiological/anatomical parameters by age
category
Age
catego
ry
Small
intest
inal
lengt
h
(cm)
Small
intest
inal
surfac
e area
(cm2)
Wei
ght
(kg)
Hei
ght
(cm
)
Bod
y
Surf
ace
area
(m2)
Neonat
e
80 352 3.5 51 0.24
Infant
(12
month
s)
120 754 10 76 0.48
Child
(5
years)
170 1495 19 109 0.78
Child
(10
years)
220 2557 32 136 1.12
Adoles
cent
(15
years)
265 3164 54.5 164 1.59
Adult 270 3393 66.5 169.
5
1.78
Findings:
Figure 1: The relationship between the
measurements of SI surface area, compared
to total body weight, height and body surface
area as compared to the adult value in each
case are shown in Figure 1.
SI surface area correlates best to body surface
area in paediatric populataions. The SI surface
area calculation does not account for the
presence of villi which would increase the
value several fold. Adult-like villi are present
in children from the age of 5; below the age of
5 the effective surface area may be
proportionally less (Thompson 1998).
Discussion: An understanding of
gastrointestinal physiology and anatomy in
paediatric patients is essential in the
development and understanding of paediatric
medicines. This data shows that dose
adjustments based on body surface area are
most appropriate in relation to drugs
absorbed from the small intestine. However,
several assumptions have been made
including; transit time, drug permeability and
drug solubility are all the same in paediatric
patients as compared to adults. Further work
is required to provide evidence for these
assumptions.
0
0.2
0.4
0.6
0.8
1
1.2
Rat
io t
o a
du
lt v
alu
e
Small intestinal surface area (cm2)
Formulating Better Medicines for Children
18. TARGETED PAEDIATRIC
BIOPHARMACEUTICS KNOWLEDGE IS
ESSENTIAL IN CRITICAL CASES
Dr Hannah Batchelor, Prof John Marriott
School of Clinical and Experimental Medicine,
College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, B15
2TT, UK
Background and Methods
The Maximum absorbable dose (MAD) can be
calculated as MAD = Peff x SISA x SITT x Cs
[Peff = effective intestinal permeability in
adults; SISA = small intestinal surface area;
SITT = small intestinal transit time; Cs =
concentration of drug within the intestinal
fluid]
Drug concentration in biorelevant fluids (Cs)
has a major influence of the bioavailability of
many drugs. The factors affecting
concentration include:
• Drug dose
• Composition of medicine formulation
• Composition of intestinal fluid
• Volume of intestinal fluid
Although drug dose and medicine
composition is known there is no data on the
composition or volume of intestinal fluids in
children. SITT is notoriously variable in
children and is influenced by fed/fasted state.
The impact of variability on MAD in paediatric
populations is considered.
Findings: Sutton (2009) highlighted that the
volume of intestinal water in adults varies
from 10-150mL with an average value of
130mL in adults. This variation is equally likely
in paediatric populations where the MAD may
vary by a factor of up to 10. Pearson (1985)
reported small intestinal times ranging from
30-240 minutes in children aged 8-14, which
would provide an 8 fold range of MAD values.
Discussion: For drugs where the clinical dose
is greater than MAD and where solubility, site
of absorption or transit time are the rate
limiting step for absorption, there is potential
for the absorbed dose to be highly variable.
Biopharmaceutical understanding is essential
when the drug, dosage and condition are
critical.
References
Sutton S. The AAPS journal. 2009;11(2):277-
85.
Pearson AD, Craft AW, Eastham EJ, Aherne
GW, Littleton P, Pearson GL, et al. Cancer
chemotherapy and pharmacology.
1985;14(3):211-5.
19. DEXAMETHASONE SOLUBLE TABLETS
FOR PAEDIATRIC USE
Zouaoui BOUREZG1,, Morgan VABRE2,
Vincent GRECK2 and Hatem FESSI1,
1- Université de Lyon, France; Université Lyon
1, UMR CNRS 5007, Laboratoire
d'Automatique et de Génie des Procédés
(LAGEP), F-69622, Villeurbanne Cedex, France
2- Only for Children Pharmaceuticals, France;
Institut Villemin, 10 avenue de Verdun, 75010,
Paris, France
Background
Dexamethasone is a potent synthetic
glucocorticoid widely used in many clinical
applications for paediatric population
fundamentally as anti-inflammatory and
immunosuppressant. It is commercially
available at different presentations essentially
tablets, injectables, eye drops… Nevertheless,
none of these forms is adapted for paediatric
use; solid forms are hardly swallowed by
children while liquid forms exhibit a very
bitter taste. The aim of this work is to offer an
alternative paediatric adapted dosage form.
Methods
Soluble tablets of Dexamethasone were
formulated, this form offered numerous
Formulating Better Medicines for Children
advantages: adequacy for paediatric use, easy
of manufacture, good stability, low cost… A
compaction simulator StylOne® was used to
mimic industrial tableting machines, better
control lubrication step and ensure a good
scale up of compaction process. A suitable
packaging should be used to reconstitute
these tablets.
Findings
Soluble tablets with good physical
characteristics were prepared. These tablets
were packaged into an adapted device; the
Shaker® which permitted an easy
extemporaneous reconstitution of an oral
solution. Thanks to the associated graduated
syringe which is perfectly adapted to the
device, a precise volume of solution can be
extracted with good accuracy. Bitterness
masking was obtained by adding adequate
amount of ion exchange resin. The masking
efficiency and suitability of such excipient for
paediatrics is discussed.
Discussion
Our formulation permitted to obtain with
standard manufacturing process:
• An excellent versatility and accuracy
of dosing,
• The use of standard excipients and
avoid the use of any preservative,
• Ensure an excellent taste masking of
this very bitter molecule.
Bibliography
Martindale, The complete drug reference.
Thirty seventh edition, volume A
(Pharmaceutical Press: 2007).
Rowe, R. C., Sheskey, P. J. & Quinn, M.
Handbook of Pharmaceutical Excipients.
(Pharmaceutical Press: 2009).
EMA, Committee for medicinal products for
human use (CHMP) Reflection paper:
Formulations of choice for the paediatric
population. (2006).
Acknowledgment
This work was funded and sponsored by the
collaborative research projet Forms4Kids
funded by the French Government (Fond
Unique Interministériel) and was certified by
Medicen Paris Region.
20. LIPID MICROPARTICLES OBTAINED BY
SPRAY CHILLING FOR PAEDIATRIC
USE
Zouaoui BOUREZG and Hatem FESSI
Université de Lyon, France; Université Lyon 1,
UMR CNRS 5007, Laboratoire d'Automatique
et de Génie des Procédés (LAGEP), F-69622,
Villeurbanne Cedex, France
Background
Lipid microparticles are widely used as
sustained release formulations by forming a
lipid matrix. Classically, surface active agents
can be used to modulate the dissolution
performance. The aim of the work is to
enhance dissolution to fit an immediate
release dosage form profile and benefit from
the masking and stabilizing effects of these
microparticles.
Methods
Lipid microspheres of a model drug are
obtained by spray chilling. Several formulation
alternatives to improve drug release from
these multiparticulate systems were
investigated in order to reduce the amounts
of surface active agents; the use of children
friendly excipients was promoted. All
formulation candidates were compared
regarding to their masking effect, stabilizing
effect and dissolution improvement.
Critical process parameters have been
screened and evaluated in order to identify
their influence on product charecteristics.
Findings
A new method to measure dispersion rate of
lipid microparticles was developed and
Formulating Better Medicines for Children
compared to dissolution test. Lipid
microparticles dispersibility was significantly
enhanced by using: soluble excipients,
swelling agents and hydrophilic polymers.
Thus, the amount of emulsifying agents can
be significantly reduced.
Good masking and stabilizing effects have
been obtained with formulation candidates.
Process parameters influenced particles sizes
and hence can influence flowability and
processability of microparticles and also their
dispersion rate.
Discussion
The spray chilling technique, a solvent-free
drug encapsulation process, was successfully
employed to obtain lipid-based microspheres
with high drug loading, efficient bitterness
masking and good stability. The use of soluble
excipients, swelling agents and hydrophilic
polymers could be an interesting way to
enhance dissolution from this multiparticulate
systems and reduce the amounts of used
surface active agents.
Bibliography
1. Jannin V, Pochard E, Chambin O. Influence
of poloxamers on the dissolution performance
and stability of controlled-release
formulations containing Precirol ATO 5. Int J
Pharm. 2006 févr 17;309(1-2):6-15.
2. Ilić I, Dreu R, Burjak M, Homar M, Kerc J,
Srcic S. Microparticle size control and
glimepiride microencapsulation using spray
congealing technology. Int J Pharm. 2009 nov
3;381(2):176-83.
3. Parab PV, Oh CK, Ritschel WA. Sustained
Release from Precirol® (Glycerol Palmito-
Stearate) Matrix. Effect of Mannitol and
Hydroxypropyl Methylcellulose on the Release
of Theophylline. Drug Development and
Industrial Pharmacy. 1986 janv;12(8-9):1309-
27.
Aknowledgment
This work was funded and sponsored by the
collaborative research projet Forms4Kids
funded by the French Government (Fond
Unique Interministériel) and was certified by
Medicen Paris Region.
21. PREVENTION OF VITAMIN D
INSUFFICIENCY IN SWITZERLAND: A
NEVER-ENDING STORY
Sebastiano A.G. Lava1,2, Giacomo D.
Simonetti2, Mario G. Bianchetti1 1Department of Pediatrics, Bellinzona and
Mendrisio, and University of Bern 2Division of Pediatric Nephrology, University
Children’s Hospital Bern and University of
Bern, Bern, Switzerland
Background
The consequences of vitamin D insufficiency
are severe. Swiss infants are therefore
prescribed 7.5–12.5 μg/day of colecalciferol
(=vitamin D3) dissolved in alcohol.
Unfortunately ≈50% of the families do not
adhere to the recommendation[1], probably
because the palatability of the alcoholic
formulation is unsatisfactory[2-3].
Methods & Results
We designed two simple studies that were
realized after ethical approval had been
granted.
In the first study[4], we compared the taste
preference of colecalciferol dissolved either in
alcohol or in vegetable-oil among 40 healthy
newborns and 30 infants. The blinded
mothers rated the facial reaction of their
children by pointing on a facial hedonic scale.
Thirty-eight newborns preferred oily
colecalciferol, with no difference between the
two preparations in the remaining two cases
(p< 0.0001). Twenty-seven infants preferred
oily colecalciferol, with no expressed
preference in the remaining three infants (p <
Formulating Better Medicines for Children
0.0005). None of the participants preferred
the alcoholic preparation.
In the second study[5], using the same
procedure, we compared the acceptance of
colecalciferol dissolved in alcohol or in
hypoallergenic medium-chain triglycerides
among 42 healthy newborns. Thirty-eight of
the 41 mothers, who brought the comparison
to completion, assigned a better score to the
oily preparation, with no difference in the
remaining three cases (p<0.0001).
Conclusions
Taste preferences are relevant already in the
first year of life and can be assessed already at
this age. From the perspective of child’s
caregivers, the taste of oily colecalciferol is
superior to that of the alcoholic formulation.
References:
1. Bartoli F, Martínez JM, Ferrarini A, Recaldini
E, Bianchetti MG. Poor adherence to the
prophylactic use of vitamin D3 in Switzerland.
J Pediatr Endocrinol Metab 2006;19:281-2.
2. Pronzini F, Bartoli F, Vanoni F, Corigliano T,
Ragazzi M, Balice P, Bianchetti MG.
Palatability of vitamin D3 preparations
modulates adherence to the supplementation
in infancy. Clin Pediatr Endocrinol 2008;17:
57-60.
3. Faré PB, Lava SA, Simonetti GD, Ramelli GP,
Bianchetti MG. Blue breath-holding spells
caused by an alcoholic vitamin D3 preparation
in infancy. Acta Paediatr 2011;100:e4.
4. Martínez JM, Bartoli F, Recaldini E,
Lavanchy L, Bianchetti MG. A taste
comparison of two different liquid
colecalciferol (vitamin D3) preparations in
healthy newborns and infants. Clin Drug
Investig 2006;26:663-5.
5. Lava SA, Caccia G, Osmetti-Gianini S,
Simonetti GD, Milani GP, Falesi M, Bianchetti
MG. Acceptance of two liquid vitamin D₃
formulations among mothers with newborn
infants: a randomized, single-blind trial. Eur J
Pediatr 2011;170:1559-62.
22. TASTE ASSESSMENT OF A FLAVORED
LOW PRICE LIQUID ORAL VEHICLE
FOR PEDIATRIC USE AMONG
CHILDREN AND PARENTS
Marina G. de Medeiros, Deborah S. Garruti,
Patrícia M. P. Thé, Maria Aparecida A. Josino,
Solange Cecilia C. Dantas, Said G. C. Fonseca,
Cristiani C.G.O. Lopes, Helena L. L. Coelho.
(Research group Melhores Medicamentos
para Crianças (MeMeCri)- Federal University
of Ceará (UFC)- Fortaleza, Brasil).
Background: Lack of oral formulations
suitable for children led to the use of
extemporaneous formulations. Palatability is
a very important factors for pediatric
compliance. The study aims to determine
acceptability and preference of an oral liquid
vehicle under development in three flavors
among children and parents.
Methods: Flavors were cherry, mint and
strawberry, chosen based on preliminary
assessment at laboratory. Overall acceptance
hedonic tests were carried out using a hybrid
facial gender-specific seven-points hedonic
scale. Data were submitted to ANOVA,
Tukey's test (p < 0.05) and frequency
distribution. Ranking Preference was also
performed, with results analyzed by
Friedman's test. The study was approved by
ethic committee and written consent was
obtained from volunteers´ guardians.
Findings: 58 health children age from 4 to 12
and 21 parents participated. All samples were
well accepted by both children and parents,
with averages ranging between “liked” and
“loved” categories. Among children, all
samples showed more than 70% of responses
between "like" and "loved". There was
significant difference among samples being
mint the most accepted, with 88% of
responses in the acceptance region and 43%
only in "loved". There was no significant
Formulating Better Medicines for Children
difference in behavior between age groups.
Mint was the most preferred, but without
statistical significance. Among parents,
samples were equally accepted and preferred.
Discussion: Age had no effect on the
acceptability among children. Parents and
children accepted well all flavors. Children
preferred mint and parents showed no
preference. Further studies are needed to
assess the acceptability of extemporaneous
formulations prepared from the vehicle with
the medicine.
23. IN VITRO DEPOSITION TESTING OF
TWO COMMERCIAL DRY POWDER
INHALERS USING PHYSICAL MOUTH-
THROAT MODELS AND SIMULATED
INHALATION PROFILES
Antje Below, Deborah Bickmann, and Joerg
Breitkreutz
Objectives: In vitro product performance
investigations of the Novolizer® have shown
that a realistic
pediatric upper airway model has no
additional benefit in inhaler testing compared
to the idealized
model [1]. Two further dry powder inhalers
(Easyhaler®, Twisthaler®) with different
airflow
resistances, formulations and designs were
investigated to proof these findings.
Methods: Inhalation profiles of a 4-year-old
boy were recorded with a pneumotachograph
and
simulated by an electronic lung. The idealized
and realistic models represent the upper
airway
geometry of 4-5-year-old children. These
inlets were connected to a next generation
impactor (NGI)
and a steady flow rate of 40 L/min
(Easyhaler)/60 L/min (Twisthaler) was applied
through the NGI.
Particles passing the model (pulmonary
deposition, PD) were captured in the NGI.
Deposited mass
was collected and determined by HPLC and
related to label claim.
Results: The generated inhalation profiles
showed peak inspiratory flow rates/inhalation
volumes of
9 L/min/130 mL (Easyhaler) and 24 L/min/320
mL (Twisthaler). No differences in pulmonary
deposition (PD) were observed using the
Easyhaler and Twisthaler with both pediatric
models. PD is
20% using the Easyhaler and 4,5% using the
Twisthaler. In comparison to measurements
with steady
flow rates through the idealized model the PD
using simulated profiles is reduced by 8%
(Easyhaler)
and by 15% (Twisthaler).
Discussion: For two further multidose DPIs
(Easyhaler, Twisthaler) it could be shown that
flow rate
influenced the pulmonary deposition more
than the type of the model.
[1] Below et al., 2011, “In vitro performance
of a dry powder inhaler using mouth-throat
models of 4- 5-year-old children”, 3rd EuPFI
conference, Straßbourg
24. EXCIPIENT SCREENING FOR
INDIVIDUALLY DOSING BY THE SOLID
DOSAGE PEN
Eva Julia Laukamp and Jörg Breitkreutz
Objectives: In paediatric as well as in
personalised medicine individual dosing is a
key topic. Recently, the Solid Dosage Pen was
introduced as device for individual dosing [1].
To develop paediatric drug formulations for
this novel device excipient screening for hot
melt extrusion was established with the
model drug carbamazepine – an
anticonvulsant frequently used in paediatrics.
Formulating Better Medicines for Children
Methods: Mini-moulds and longitudinal
moulds were produced containing 10%
Carbamazepine in combination with the
excipients mannitol, polyethylene glycols
(PEG), Gelucire®50/13 (stearoyl macrogol-32
glycerides). Dissolution profiles of mini
moulds were determined using a paddle
apparatus, 75 rpm at 37°C in demineralised
water (n=5). The cuttability was assessed by
maximum cutting force and force-distance-
diagrams of the longitudinal moulds
implementing a newly developed cutting tool
(n=10).
Results: While Gelucire®50/13 and mannitol
formulations showed high t75% dissolution
values (103 and >360 min), PEG formulations
showed immediate release (5 and 7 min).
Cutting forces were low for Gelucire®50/13
and PEG formulations (up to 8 N). In contrast,
mannitol formulations reached 26 N as
maximum. Addition of mannitol showed an
impact on the maximum cutting force in
Gelucire and PEG formulations (up to 11 N).
Discussion: Specifications for immediate
release cuttable dosage forms were defined
as t75% values below 60 min and a maximum
cutting force between 10 and 20 N. One
formulation fulfilled all specifications and will
be further investigated. One disadvantage of
the screening set-up was that moulds could
not be prepared for highly viscous excipients
in hot melt extrusion. In future, screening set-
up shall also be applied to hot melt
extrudates.
Reference:
[1] Wening K, Breitkreutz J. Int J Pharm
395:174-81 (2010)
25. EVALUATION OF A NOVEL
PHARMABURST® BASED ODT
FORMULATION FOR WEIGHT-
SPECIFIC DOSING OF AMOXICILLIN IN
CHILDREN
Praveen Saligram – SPI Pharma
Background
Swallow tablets have always been a difficult
dosage form for pediatric patients due to
difficulty in swallowing and division of the
dose based on the weight of the subject is not
a possibility. The formulation is an ODT mini-
pellet of Amoxicillin employing Pharmaburst,
which disintegrates within 10 seconds in the
mouth. This provides a way of accurate
weight-based administration of Amoxicillin
and brings about improved safety and efficacy
during dose-titration, as compared to either
breaking of large swallow tablets or
administration of liquids.
Methods
ODT mini-pellets containing 15mg of
Amoxicillin (as trihydrate) were formulated
using Pharmaburst 500 and other excipients.
These mini-pellets were evaluated for
Average weight, Weight variation,
Disintegration time, Assay and Uniformity of
dosage units.
Findings
The average weight was found to be 50.93 mg
as against a target weight of 50.00 mg; weight
variation was within 2.0% w/w, while the
disintegration time was 4 seconds. The assay
was 99.0% which is within the limits of 95.0–
105.0% and the uniformity of dosage units
had a mean of 96.0% with an acceptance
value (AV) of 7.97 and ranged from 92.8–
98.6%.
Discussion
The Pharmaburst based ODT mini-pellet
formulation provided a novel way of
administering Amoxicillin to children for
weight-based dosing. The formulation had
Formulating Better Medicines for Children
acceptable assay and uniformity of dosage
units, thus providing more accurate means of
Amoxicillin dose titration. In addition, the
formulation overcomes the difficulty of
swallowing in children as these are mini-
pellets meant for administration as an ODT
with a disintegration time of 4 seconds.
Reference
1.WHO Model List of Essential Medicines for
Children from
<http://www.who.int/medicines/publications
/essentialmedicines/en/index.html>
2.World Health Organization (WHO) Report of
the Informal Expert Meeting on Dosage Forms
of Medicines for Children from
http://www.who.int/selectionmedicines/com
mittees/expert/17/application/paediatric/Dos
ageformreportDEC2008.pdf>
26. DISSOLUTION EVALUATION OF
ACTIMASK 92M, A NOVEL,
AQUEOUSLY-PROCESSED TASTE-
MASKED ACETAMINOPHEN
John Tillotson – SPI Pharma
Background
With orally-dispersible and chewable
formulations, pediatric patients often require
taste-masked API’s. Typical strategy in taste-
masking is to coat the API with a hydrophobic
substance. While taste-masking is achieved,
this can lead to a significant reduction in the
dissolution rate. Actimask 92M technology
employs a hydrophilic taste-masking barrier,
which taste masks effectively and
simultaneously allows for rapid release. The
present research studied the effect of
different dissolution media on the release of
Acetaminophen from the Actimask 92M taste-
masked system, as compared to uncoated
Acetaminophen powder.
Methods
Actimask 92M taste-masked Acetaminophen
and Acetaminophen powder both equivalent
to 250mg of Acetaminophen were dissolution
tested under the following conditions:
Temperature 37.5°, Apparatus 2: 50rpm,
900mL of the respective dissolution media (pH
6.8 phosphate buffer – oral pH, pH 0.1N HCl –
gastric pH, pH 5.8 phosphate buffer –
compendial immediate release dissolution
media).
Findings
In pH 6.8 phosphate buffer at 1 minute,
Actimask 92M release was 14.1% compared
to 51.7% for uncoated Acetaminophen. In pH
0.1N HCl, Actimask 92M release was found to
be similar to uncoated Acetaminophen (f2 =
58). In pH 5.8 phosphate buffer, both
Actimask 92M and uncoated Acetaminophen
met dissolution requirements for an
immediate-release Acetaminophen tablet: at
30 minutes 100.3% and 100.4%
Acetaminophen release, respectively.
Discussion
Actimask 92M provided for both taste
masking (significantly reduced 1-minute
acetaminophen dissolution at oral pH as
compared to uncoated acetaminophen), while
still providing for a rapid release (similar
dissolution to uncoated acetaminophen at GI
pH, and meeting compendial requirements for
the dissolution of immediate-release
acetaminophen tablets).
27. DEVELOPMENT OF ANTI-TB ORAL
FORMULATIONS FOR CHILDREN.
Said G. Fonseca, Maria A. A. Josino, Livia Aline
A. Batista, Marina G.C. Medeiros, Tulio Flávio
A. L. Moura, Helena Lutescia L. Coelho, and
Fernanda N. Raffin. (Research group Melhores
Medicamentos para Crianças (MeMeCri)-
Federal University of Ceará (UFC)- Fortaleza,
Brasil), Federal University of Rio Grande do
Norte (UFRN).
Formulating Better Medicines for Children
Background;Tuberculosis is a disease that
affects people around the world, mainly in
poor countries, treated basically with
Isoniazide, Rifampicin and Pyrazinamide for
which no appropriate dosage forms are
available for children. The objective of this
work is to develop a combined formulation of
these tuberculostatics suitable for oral use in
children, mainly after 3 months old.
Methods; The compatibility of rifampicin with
different polymers (chitosan and
hypromellose HV at 2%, povidone K-30,
hypromellose LV and methylcellulose LV at
10%) was assessed by DSC; The stability of
rifampicin 20mg/ml associated with isoniazid
10mg/ml and pyrazinamide 30mg/ml under
different pH values (5-9) was evaluated using
HPLC. Formulations of extemporaneous
suspension containing rifampicin granules
obtained with the studied polymers are been
evaluated in terms of dose homogeneity,
sedimentation rate, rheology, dissolution
profile and stability.
Mainly partial results are presented:
Povidone promoted an increase in the
solubility of rifampicin, cellulose derivatives
increased viscosity of the suspension without
significant effect on the retention capacity of
rifampicin, while chitosan showed the ability
to retain this drug. The monitoring of the
amount of three drugs in solutions with
different pH values demonstrated that higher
pH values give longer stability to the
formulation.
Discussion: The results indicate that it is
possible to obtain suspensions in which
rifampicin be retained in granules avoiding
interaction with the other drugs. Once
chitosan is soluble at acidic pH, rifampicin
would be released immediately in the
stomach. A spectrophotometric method to
the simultaneous analysis of the dissolution
profile of the three drugs is in development.
28. EU PEDIATRIC REGULATION: DO
CHILDREN REALLY BENEFIT(1)?
L Schrier¹, M Holmes¹, A Mui¹, JMA van
Gerven¹, AF Cohen¹; ¹Centre for Human Drug
Research (CHDR), Leiden, the Netherlands
Background: Many medicines used in
pediatrics have not been tested in children
and children are often denied access to new
medicines. The EU Pediatric Regulation (2007)
grants patent extension when pediatric
labeling is provided for new or off-patent
drugs. We investigated the effectiveness of
this program in stimulating pediatric research
overall and for CNS medications in specific.
Methods: Pediatric Investigational Plans (PIPs)
submitted until March 2012 were retrieved
from the EMA website (1) and classified
according to the Anatomical Therapeutic
Chemical system. Submitted data that
resulted in PIP approval for indications in
neurology, pain and/or psychiatry were
examined. In addition, clinical trials registries
(2, 3, 4) and the EMA Pediatric Needs List (5)
were searched for these PIPs.
Findings: 760 applications were submitted
with most frequent drug groups including
respiratory, genito-urinary and sex-hormones,
and antineoplastic/immunomodulating drugs.
10% of submitted applications were for CNS
indications. Almost all approved CNS PIPs
(28/31) had ongoing or completed studies.
Approved PIPs represented 15% of off-patent
priority CNS medicines with the largest needs
areas (psychiatry and epilepsy) researched the
least.
Discussion: With exception of respiratory
drugs, a discrepancy was found between
drugs most frequently used by children (i.e.
respiratory drugs, anti-infectives and
dermatologicals (6)) and drugs approved for
research in children. In addition, this publicly
funded stimulation program is not effective in
stimulating pediatric research for off-patent
Formulating Better Medicines for Children
or new CNS medicines. Evaluation of
approved PIPs for other therapeutic fields and
qualitative assessment of the expected impact
of newly acquired data on clinical practice is
ongoing.
References:
1. EMA Website:
http://www.emea.europa.eu/ema/index.jsp?
curl=pages/medicines/landing/pip_search.jsp
&mid=C
0b01ac058001d129 (Accessed 04/2012).
2. EudraCT Website:
https://eudract.ema.europa.eu/
3. WHO ICTRP Website:
http://www.who.int/ictrp/en/
4. Clinicaltrials.gov Website:
http://clinicaltrials.gov/
5. PCO: Revised priority list for studies into
off-patent paediatric medicinal products (last
updated
09-02-2012).
http://www.ema.europa.eu/docs/en_GB/doc
ument_library/Other/2009/10/WC500004017
6. Boots, I., Sukhai, R.N., Klein, R.H., Holl, R.A.,
Wit, J.M., Cohen, A.F., & Burggraaf, J. 2007.
Stimulation programs for pediatric drug
research—do children really benefit? Eur.J
Pediatr., 166, (8) 849-855 available from:
PM:17225950
29. EU PEDIATRIC REGULATION: DO
CHILDREN REALLY BENEFIT (2)?
L Schrier¹, A Mui¹, M Holmes¹, JMA van
Gerven¹, AF Cohen¹; ¹Centre for Human Drug
Research (CHDR), Leiden, the Netherlands
Background: The lack of appropriate pediatric
formulations is a major obstacle for the study
and use of drugs in children. The EU Pediatric
Regulation (2007) grants patent extension
when pediatric labeling is provided for new
drugs or for off-patent drugs that are listed on
the Priority List (1). We investigated the
effectiveness of this regulation in stimulating
pediatric formulation research for off-patent
drugs.
Methods: The Priority List was searched for
off-patent drugs for which a need for the
development of age-appropriate
formulation(s) was indicated (referred to as
“formulation priority drugs”). Pediatric
Investigational Plans (PIPs) submitted for
these drugs were retrieved from the EMA
website (2) and submitted data that resulted
in approval was searched for planned
formulation research. Clinical trials registries
(3, 4 and 5) and European and/or Dutch SPCs
were searched for information on the status
of planned studies and pediatric labeling.
Findings: Fifty-two% (179/339) of off-patent
drugs on the Pediatric Needs List were
formulation priority drugs. PIP applications
were submitted for 43 of these drugs of which
half were approved. Most of approved PIPs
(14/16) have ongoing or completed studies; 4
have resulted in European or national
pediatric labeling regarding formulation so
far.
Discussion: The Priority List is an important
tool to direct much needed pediatric
formulation research for off-patent drugs.
Despite the important financial incentive (10
years of patent extension), the regulation has
not led to a substantial increase of
commercially available age-appropriate
formulations for children that need them the
most.
References:
1. PCO: Revised priority list for studies into
off-patent paediatric medicinal products (last
updated
09-02-2012).
http://www.ema.europa.eu/docs/en_GB/doc
ument_library/Other/2009/10/WC500004017
2. EMA Website:
http://www.emea.europa.eu/ema/index.jsp?
Formulating Better Medicines for Children
curl=pages/medicines/landing/pip_search.jsp
&mid=C
0b01ac058001d129 (Accessed 04/2012).
3. EudraCT Website:
https://eudract.ema.europa.eu/
4. WHO ICTRP Website:
http://www.who.int/ictrp/en/
5. Clinicaltrials.gov Website:
http://clinicaltrials.gov/
30. OPTIMIZING THE TASTE-MASKED
FORMULATION OF ACETAMINOPHEN
USING SODIUM CASEINATE AND
LECITHIN BY EXPERIMENTAL DESIGN
T.H. Hoang Thi1, M. Lemdani2, M.P. Flament1 1Inserm U1008, College of Pharmacy, Lille,
France 2Laboratoire de Biomathématiques, College of
Pharmacy, Lille, France
Email: [email protected]
Objective: In our previous study, the
association of sodium caseinate and lecithin
was demonstrated to be promising for
masking the bitterness of acetaminophen. A
factorial design also allowed screening for the
most important design variables that affect
the released amount up to ten minutes, i.e.
quantity of sodium caseinate and lecithin. The
present work aims therefore to determine the
quantity of excipients for the optimal taste-
masked formulation.
Methods: Taste-masked powders were
produced by spray-drying aqueous solutions.
Experimental conditions were established by a
sequential simplex design. The percentage of
released amount during the first two minutes
was defined as the response. The release
study was carried out by a continuous flow
system with PBS pH 7.4 for mimicking the
realistic conditions within the mouth. Drug
release study was also performed in the HCl
pH 1.0 media under sink conditions in order to
examine the immediate release of taste-
masked formulations.
Results: The optimal formulation was
obtained containing a 1:1.6:2.5 ratio of drug,
sodium caseinate and lecithin, respectively.
The percentage of released amount during
the first two minutes was 4.15 ± 0.96 %, being
7-fold less than the unmasked drug particles.
The optimal formulation was also shown to be
immediately released once reaching the
stomach, i.e. 96.5 ± 1.2 % of drug released in
HCl pH 1.0 media after 45 minutes.
Conclusions: An optimized formulation for
masking the bitterness of acetaminophen was
successfully achieved by simplex approach.
The taste-masked powder is intended to
develop a multi-particulate dosage form for
paediatric use.
31. DEVELOPMENT OF SPHERICAL
FORMULATION OF CANDESARTAN
CILEXETIL FOR CHILDREN
Takahiro Endo1, Masahiro Goto1, Hideki
Nakajima2, Yoichi Ishikawa2, Hidefumi
Nakamura2, Junichiro Fujimoto 2, Masato
Takahashi1 1 Toyo Capsule Co.,Ltd. , Shizuoka, Japan. 2 National Center for Child Health and
Development, Tokyo, Japan.
We have developed a technology to produce
small sphere for pediatric formulation
(Spherical Formulation: SF). SF is smaller than
a tablet, and the weight per each SF is better
controlled compared to granules. SF can
contain solid or liquid in a sphere. SF is
suitable for poorly soluble drugs, or drug
unstable to heat and water. In this
presentation, we introduce the SF of
candesartan cilexetil that is being developed.
We made a special plant to manufacture SF
using combination of vibration and
refrigeration (Fig.1). This plant can produces
different sizes of sphere with a diameter of 1-
Formulating Better Medicines for Children
10 mm and weight of 0.5 mg -200 mg. The
speed for production is 30 pieces per second.
We can also add several tastes and flavors for
masking.
We could produce fine formulation of
candesartan cilexetil using our method. SF
could contain as small amount of candesartan
cilexetil as 0.125 mg/ SF, much smaller unit
compared to commercially available tablets
without adding excess heat and pressure.
Stability tested by the accelerated test at a
temperature of 42℃±2℃ and humidity of
75%RH ± 5%RH of the 12 mg SF (0.125 mg/SF
× 96) was comparable with the commercially
available Blopress 12 mg tablets (Fig. 2).
Results of dissolution test is also compared
(Fig.3).
We could successfully produce candesartan
cilexetil SF with comparable stability and
dissolution compared to commercially
available products. SF may be a good
alternative formulation for candesartan
cilexetil for smaller children
32. MEDICINES FOR CHILDREN IN JAPAN
– NEW APPROACH TO BITTER
MEDICINES
M. Habara1, H. Ikezaki1, M. Yoneko2, S.
Murata2 and J. Kojima2 1Intelligent Sensor Technology, Inc. JAPAN 2National Center for Child Health and
Development
Background and Objectives: In Japan, many
medicines are not available commercially for
pediatric patients and over 75% of pediatric
medicine prescriptions are off-label use. Since
infants and young children do not easily
swallow a solid dosage form, powder forms
are prepared from commercially available
solid tablets and capsules (by crushing tablets
and emptying capsules). These powders are
divided into single dosages and packed.
Preparing packages with accurate dosages for
each patient is a duty of the Japanese
pharmacist. The prepared powders
sometimes have a bitter taste, resulting in
more patient non-compliance. This study
assessed masking of the bitter taste of
medicines using a taste sensing system.
Methods: Propranolol was used as the bitter
taste control. Orange juice, milk, chocolate
milk (cocoa), sugars and sugar alcohols were
each combined with propranolol, and the
masking effect was measured using the TS-
5000Z Taste Sensing System (Intelligent
Sensor Technology, Inc. Japan).
Findings: Cocoa effectively reduced the
bitterness of propranolol (Fig. 1). Sugars and
sugar alcohols exhibited concentration-
dependent masking effects too (Fig. 2).
Formulating Better Medicines for Children
Discussion: Cocoa, sugars and sugar alcohols
can mask the bitterness of propranolol.
Compared to human tasting panels, this
testing approach has advantages of accuracy,
relatively low cost, and lack of risk. The results
suggest that a taste sensor can provide basic
information on assessment of masking the
bitter taste of medicines.
33. DETERMINING SURFACTANT EFFECT
IN RESIDUAL OIL INCLUSION DURING
THE DEVELOPMENT OF TASTE
MASKED MICROSPHERE PROCESSING
METHOD.
Peter M. Ikamati 1, Yvonne Perrie 1, Roderick
B. Walker 2 and Daniel J. Kirby 1,
1Aston Pharmacy School, Aston University,
Birmingham, B4 7ET, UK; 2 Faculty of
Pharmacy, Rhodes University, Grahamstown,
South Africa, 6140
Presenting author: [email protected]
In order to overcome the bitter taste and
odour associated with drugs such as
flucloxacillin, a novel, taste masked alginate
microsphere formulation is proposed.
However, when producing such systems by
emulsification processes, oil entrapment
presents a significant challenge. The aim of
this study, therefore, is to investigate the
impact of surfactant on residual oil
accumulation during microsphere processing.
Microsphere processing using emulsification,
w/o (1:7 % v/v), followed by external gelation
was applied. Rotor-stator technology
(Polytron PT 3000, Kinematica AG,
Switzerland) was used at 1500 rpm for 10
minutes each in the emulsification and
dispersion stages. A polymer solution of
alginate (2% v/v) and HPMC (1% v/v) mixed in
a ratio of 9:1 was used. Span 80 mixed with a
series of homologous polysorbates was used
at varied mixed emulsifier concentration, tied
to HLB value of 7 (Sunflower oil’s HLB), to
ensure a stable emulsion.
Polysorbates with long alkyl chain length
show lower residual oil. This is particularly
evident when comparing tween 20 and tween
80, with the longer chain length possibly
providing a more thermodynamically stable
interfacial film, resulting in lower oil content
and smaller particle size when compared to
the shorter chain polysorbate. This trend
could be due to the similar chain length to
span 80. A further reduction in residual oil
content was also seen when combining both
tween 20 and tween 80 with span 80, with the
shorter chain polysorbate potentially inserting
itself between the longer chain surfactant
molecules, thereby further stabilising the
interfacial film.
Formulating Better Medicines for Children
34. THE DEVELOPMENT OF A FLOW
THROUGH DISSOLUTION TEST
METHOD FOR THE DETERMINATION
OF FLUCLOXACILLIN RELEASE
PROPERTIES OF TASTE MASKED
MICROSPHERES
Peter M. Ikamati 1, Yvonne Perrie 1, Roderick
B. Walker 2 and Daniel J. Kirby 1,
1Aston Pharmacy School, Aston University,
Birmingham, B4 7ET, UK; 2 Faculty of
Pharmacy, Rhodes University, Grahamstown,
South Africa, 6140
Presenting author: [email protected]
Flucloxacillin has a bitter taste and odour,
thus requiring a suitably taste masked liquid
dosage device [1]. This study aimed to
develop a robust dissolution method for the
assessment of flucloxacillin release during
development of a novel taste masking
microsphere formulation. To this end, a Flow
through cell (FTC) that would be suitable for
micro-particulate formulations and micro-
sized devices was investigated.
A disintegration test of flucloxacillin 500 mg
hard gelatin capsule (Athlone Laboratories
Limited) was used as a surrogate marker of
dissolution for establishing an Assumed IVIV
relationship [2]. An FTC, CE 7 Smart, equipped
with a CY 7-50 pump and a Cell size of 22.6
mm (Sotax AG, Switzerland) was used in the
closed loop with various media (compendial
and biorelevant) and flow rates (2 to 32
mL/min), with sampling done at 5 to 60
minutes, followed by HPLC analysis.
Flow rate effect appears between 2 to 8 and
16 to 32 mL/min, with the former revealing
longer disintegration times. Disintegration
was faster and precise in biorelevant media
and was more than likely due to ionic strength
and surfactant effects. Disintegration in
FaSSGF & FaSSIF at 4 and 8 mL/min were
more predictive of in vivo [3]. Complete drug
release was obtained within 15 minutes for
both 4 and 8 mL/min, which correspond to
velocities of 1 & 2 cm/min respectively,
mimicking physiological mixing rates equating
to 1 cm/min in the FTC.
REFERENCES
1. Nunez-Vergara L.J.et al 1988: General
Pharmacology-vol 19 (3), 447-449, British
Library.
2. Yu, H. and Joves R. (2004): The STATs of
cancer--new molecular targets come of age.
Nat Rev Cancer, 4(2): 97-105 in Emami J.
(2006); In vitro - In vivo Correlation: From
Theory to Applications; J Pharm Sci 9(2):169-
189 [www.cspscanada.org]
3. Digenis G. A., Sandefer E. P., Page R. C., Doll
W. J., Gold T. B., and N. B. Darwazeh (2000):
Bioequivalence Study of Stressed and
Nonstressed Hard Gelatin Capsules Using
Amoxicillin as a Drug Marker and Gamma
Scintigraphy to Confirm Time and GI Location
of In Vivo Capsule Rupture, Pharmaceutical
Research, Vol. 17, No. 5,pgs 572-582.
35. THE IMPACT OF THE EUROPEAN
PAEDIATRIC REGULATION ON
AUTHORISED MEDICINES FOR
CHILDREN – UK EXPERIENCE
Sarah Branch
The Paediatric Regulation has been in force
for five years and the objective of this
presentation is to consider its impact on the
number of medicines authorised for children
in the UK.
We have evaluated the progress of products
through the regulatory steps indicated in
Figure 1 which summarises the situation at
May 2012.
Figure 1: Progress with PIP submissions, MA
applications and Granted of the paediatric
reward in the UK.
Formulating Better Medicines for Children
In the first five years of the Regulation, 74% of
PIP submissions have been for new medicinal
products, 24% for existing products. Only 2%
of submissions are for off-patent drugs for
new paediatric use (Paediatric Use Marketing
Authorisations). The latter figure is
disappointing since there is a clear need for
age-appropriate formulations of older
established medicines, however the first
PUMA was given a European authorisation in
September 2011.
UK, like other member states, asks for
compliance to be checked by the European
Paediatric Committee (PDCO) before
accepting a valid MA application. PDCO has
issued full compliance opinions for 32
products. About 70% of these have now
completed either decentralised or centralised
European procedures leading to product
information updated with results of paediatric
studies in PIPs. As a consequence in the UK
there are 10 products with additional or
extended paediatric indications, 9 with
additional information on paediatric studies
and 6 with new pharmaceutical forms suitable
for younger-age children.
In the UK there have been 11 applications
made to the patent office for paediatric
extensions, almost half of the products which
have include information from PIPs. 10
rewards have been granted. Compared with
the situation two years’ ago, full PDCO
compliance opinions and applications in the
UK supported by PIPs have approximately
doubled and the number of paediatric
extensions is somewhat higher
proportionately.
The number of approved PIP submissions has
steadily increased indicating that a substantial
number of paediatric studies remain to be
completed. Thus, while some progress is
being made with the authorisation of properly
researched and developed medicines for
children, it is likely that it will take at least
another 5 year period before a significant
impact will be seen due to the number of
these deferred studies.
36. A QUESTIONNAIRE ON FACTORS
INFLUENCING CLINICAL
DEVELOPMENT OF MEDICINES FOR
CHILDREN IN JAPAN
Maki Yoneko1, Nao Tuschida1, Nanako
Nagafuchi1, Michihiro Kitagawa1, Tetsuharu
Nagamoto2 and
Jun Kojima1,3
1: National Center for Child Health and
Development, 2:Okinawa Children's Medical
Center, 3: Department of Neurological
Surgery, Nihon University School of Medicine
North America, Europe and Japan accounts
for a large majority (79%) of the global
pharmaceuticals market (IMS Health, 2010). In
recent years, both FDA and EMA have
implemented regulations to oblige and/or
incentivize companies to develop drugs for
the pediatric population. In contrast, Ministry
of Health, Labour and Welfare of Japan has
not introduced comparable measures. On top
of insufficient regulatory commitment,
difficulty in conducting pediatric clinical trials
and the small yet unknown size of pediatric
market have often been cited as major
hindrances. In addition, many drug company
staffs lack understandings on the practical
difficulties faced by children. We created a
brief DVD video to inform stakeholders of the
clinical realities facing the pediatric
population. It contained descriptions of
extemporaneous formulations, including
typical procedures for crashing tablets and
decapsulation, as well as stability of resulting
Formulating Better Medicines for Children
powders. We gathered drug company staffs
for a viewing. The participant drug company
staffs then completed a questionnaire,
through which we gathered their opinions on
the video and on challenges faced by their
companies when developing medicines for
children. At this EuPFi meeting we would like
to present the questionnaire result, and offer
the video, which includes scenes with customs
peculiar to Japan, such as powder packing
machine and swallowing-aid jelly, for a
viewing. Your views on the video (and more)
are appreciated.
38. CONSIDERATIONS OF CHILDREN AND
PARENTS TO PARTICIPATE IN A
PEDIATRIC FORMULATION TRIAL
Lidwien M. Hanff1, M.Cavazza2, R.Pieters2,
C.M. Zwaan2
Hospital Pharmacy1, Paediatric Oncology2,
Erasmus University Medical Center
Rotterdam-Sophia Children’s Hospital, The
Netherlands
Correspondence: [email protected]
Background:
A bioequivalence study was performed
comparing 6-mercaptopurine liquid with 6-
mercaptopurine capsules in 20 pediatric
oncology patients with acute lymphatic
leukemia (ALL). All patients were treated for
8 weeks, using both formulations
consecutively in a cross-over setting. The
burden for patients was considered low. In
this report, the reasons for withholding
informed consent were analysed, to improve
the understanding of the motivation for
parents and children to participate in
formulation trials.
Methods
All eligible patients with ALL were asked to
participate in the study during 2009-2012 by
their attending pediatric oncologist. If they
refused, the reason was documented by the
research nurse.
Results
59 patients have been invited for inclusion
and 35 (59%) patients refused (age 3-16yr,
median 5yr ). 24 patients (age 1-14yr, median
4yr) participated in the study.
The main reasons for refusal were:
- no changes wanted in their routine
(n=18)
- preference of (older) children for
capsules (n=3)
- fear of parents for lower compliance
with a different formulation (n=2)
- logistic reasons (n=8)
- need for extra bloodsampling (n=4)
The main motivation to participate in the
study for patients and parents was the
recognized need to overcome the current
formulation problems, both for their own
child, as for future pediatric ALL patients.
Discussion : The number of patients to refuse
participation in this trial was higher than
expected, given the assumed low burden. The
main reasons were logistic reasons and the
unwillingness to change routine. In designing
formulation studies, these reasons need to be
specifically addressed.
39. PRINTING OF PERSONALIZED
MEDICINE FOR PAEDIATRIC AND
GERIATRIC USE
Natalja Genina, Daniela Fors, Petri Ihalainen,
Jouko Peltonen, and Niklas Sandler
The main goal of this study was to investigate
inkjet and flexographic printing technologies
in fabrication of paediatric and geriatric drug-
delivery systems through incorporation of
different doses of active compounds on
various substrates and layering them with a
gastrointestinal tract insoluble polymer to
control release properties of drug substances.
Formulating Better Medicines for Children
Riboflavin sodium phosphate (RSP) and
caffeine were used as model drugs in ink
formulation. Printing of active compounds
was done by depositing drug solution into 1
cm2 cellulose substrate areas using a Dimatix
inkjet printer with different drop spacing. The
printed drugs were coated with ethylcellulose
(EC) polymer of different thickness using
flexographic printing. Release studies were
carried out by using a Sotax AT7 dissolution
tester.
Different strengths of the drug were produced
by regulating the drop spacing of the printing
ink formulation. The immediate release
behavior was shown by the deposited drug
substances without any polymer coating. The
EC layers printed using flexographic printing
resulted in a sustained drug release with
increasing amount of layers as anticipated.
The release profile was different for the
different substrates used. The results indicate
that the drug release is therefore influenced
by the properties of the substrates in
combination with the polymer layering.
The application of combined printing
technologies to deposit a different amount of
drug substances onto porous cellulose
substrates is a promising approach in the
production of personalized medicines with
distinct characteristics, high dose precision
and tailored release behavior.
40. TASTE ASSESSMENT OF
METHYLXANTHINES USING AN
ELECTRONIC TONGUE
Xolani Dereck Gondongwe1, Duncan Craig1,
Paul Flanders2, David Wright1, Paul Grassby1 1School of Pharmacy, University of East Anglia,
Norwich, UK 2Rosemont Pharmaceuticals, Ltd, Leeds, UK
Background and Objectives
Electronic tongues or taste sensors (TS) may
provide a robust and reliable means of taste
assessment during the pharmaceutical
formulation process. In investigating this
potential approach it is necessary to elucidate
the precise mechanism of drug-sensor
interaction. In this study, we obtained data
from the Insent TS-5000Z of caffeine,
theophylline and theobromine, to examine
any potential structure-sensitivity
relationships. Following work by Woertz et
al[1], we have also examined the possible role
of electrolyte dissociation in the taste sensing
process.
Methods
Internal solutions, positive, negative and
reference solutions were supplied by Insent
Inc (Atsugi-shi, Japan). Anhydrous
theophylline and theobromine (Sigma Aldrich,
UK), caffeine and caffeine citrate (Fisher
Scientific UK) were of analytical grade. Test
solutions ranging from 0.05mmol/L to
25mmol/L were prepared using deionised
water or phosphate buffer solution (pH=7.0).
Results
Principle component analysis (PCA) taste
profile demonstrated similarity between
theophylline and theobromine, with basic
bitterness as predominant taste. Caffeine had
a different profile with basic and acidic
bitterness as its predicted taste. When buffer
was added to all three methylxanthines the
predominant taste response shifted to basic
bitterness with astringency. When examining
increasing concentrations of methylxanthines
this was not reflected by increased outputs
from the four sensors. However on addition of
buffer, the sensor responses pattern was
altered.
Discussion and Conclusions
These results have demonstrated that the TS
can detect taste profiles in similar molecules
and indicated that these profiles were also
influenced by the presence of buffer. It was
interesting that no dose-relationship could be
observed to methylxanthines. Addition of
Formulating Better Medicines for Children
buffer seems to have affected the degree of
ionisation, hence altering sensor response
patterns.
References
1. Woertz, K., et al., Rational development of
taste masked oral liquids guided by an
electronic tongue. International Journal of
Pharmaceutics, 2010. 400(1-2): p. 114-123.
41. ELECTRONIC TASTE ASSESSMENT OF
BILAYER ORODISPERSIBLE FILMS
Maren Preis, Katharina Schneider, Jennifer
Kukawka, Jens Broscheit, Norbert Roewer,
and Jörg Breitkreutz
Background: Bilayer films were developed,
consisting of a drug loaded layer and a
backing layer to shield the bitter drug
substance from the oral cavity and to ensure
drug release only towards the mucosal site.
Methods: Lidocaine hydrochloride (LC) was
used as model drug and implemented in a
hydroxyl propyl cellulose film base. Backing
layers were prepared from hydroxyl ethyl
cellulose (HEC), hypromellose (HPMC) methyl
cellulose (MC) and carbomer (PAA) by solvent
casting. Insent® electronic taste sensing
system was used for taste assessment. Bilayer
films were fixed on the bottom of a glass
beaker filled with 100 ml of distilled water at
36°C. Stirrer was set to 50 rpm. Drug
dissolution samples were taken at four time
points (15 s, 60 s, 180 s and 300 s).
Findings: Multivariate data analysis of taste
sensor responses revealed shielding effects
for MC, PAA and HEC backing layer
formulations: MC layers were able to avoid
drug release towards the dissolution media
for 15 s. PAA layer showed even longer
shielding times (60 s), before LC could be
detected by the electronic taste sensing
system. Data obtained from HEC backing
layers revealed shielding over 300 s. Slight
shifts could be seen for HEC samples, meaning
only minor LC release during release study.
Conclusion: It was possible to use an
electronic taste sensing system to evaluate
the shielding capacity of a backing layer in a
bilayer film to avoid bitter tasting drug release
in the oral cavity.
42. INTRODUCTION OF A NEW
DISINTEGRATION TEST FOR
ORODISPERSIBLE FILMS
Maren Preis and Jörg Breitkreutz
Background: Orodispersible films (ODFs) have
most recently become part of the
“oromucosal preparations” monograph in the
European Pharmacopoeia, but no test
methods for this new dosage form are
defined, yet. For this purpose we intended to
develop a discriminative and easy
disintegration method.
Methods: Clip weight method: ODFs were
fixed by a clip on top of a glass beaker filled
with distilled water or phosphate buffers (pH
6 - 8). Weights were fixed at the film’s bottom
side. Time till the weight was sinking down to
the beaker’s ground was measured.
Findings: Buffer media had no influence on
disintegration of Lycoat® ODFs (water: 7.4 s;
pH 6: 5.6 s; pH 7: 6.6 s; pH 8: 6.4 s). Only
phosphate buffer pH 8 had a strong influence
on HEC (water: 148.8 s; pH 6: 96.6 s; pH 7:
108.6 s; pH 8: 18.8 s). HPMC ODFs
disintegrated slightly slower in buffer media
than in water (water: 15.2 s; pH 6: 20.2 s; pH
7: 21.4 s; pH 8: 22.4 s). PAA ODFs did not
disintegrate within 10 minutes. Higher weight
lead to faster disintegration times for HEC
(148.8 s to 81.0 s) and MC (21.2 s to 6.6 s), but
did not influence HMPC (15.2 s both times)
and Lycoat® (7.4 s to 6.4 s).
Discussion: Evaluation of a new disintegration
test for ODFs was successfully performed by
Formulating Better Medicines for Children
this new method. The end point offers a clear
and objective determination of ODF
disintegration times. Therefore, clip weight
method reveals suitability for ODF
characterization.
43. MELT GRANULATION AS A SINGLE-
STEP MANUFACTURING PROCESS OF
A TASTE MASKED DOSAGE FORM
CONTAINING A HIGHLY SOLUBLE API
Carolin Eckert, Miriam Pein, and Jörg
Breitkreutz
Objectives: Due to the known characteristics
of the orphan drug sodium benzoate (SB)1,2,
it is desirable to produce a taste masked,
highly drug loaded dosage form under
exclusion of moisture. In this study the
aforementioned requirements should be
accomplished by melt granulation.
Methods: Melt granulation with 70% SB and
30% Witocan 42/44 mikrofein was carried out
in a high shear mixer (Diosna P-VAC 10) with a
heating jacket temperature of 38°C and an
impeller speed of 800 rpm. Dissolution profile
was determined using a basket apparatus
with 150 rpm at 37°C in demineralized water
(n=6). Samples were taken at predefined time
points and characterized with two electronic
taste sensing systems (Insent, αAstree).
Morphological properties were examined
using scanning electron microscopy.
Results: 83% SB are released after 30 min,
implying an immediate drug release (USP 33).
However, both etongues detect a taste
masking effect. Figure 1 shows a PCA map
composed from all utilized sensor signals.
Samples with short dissolution times display
similar sensor responses. Several sensors can
detect a difference between water and a
drug-free lipid formulation.
Discussion: A taste masked immediate release
dosage form containing highly soluble SB was
developed using melt granulation. An entire
taste masking was not achieved, because
some SB crystals on the granule surface are
not fully covered, which was observed by
SEM. The profit of the single step process
instead of extrusion/spheronization comes to
a small expense of complete taste masking
properties.
References:
1. Boneh et al., Molecular Genetics and
Metabolism 94: 143-147 (2008)
2. Breitkreutz et al., Eur J Pharm Biopharm 56
(2): 255-260 (2003)
44. DEVELOPMENT OF A PALATABLE
MIDAZOLAM FORMULATION FOR
PAEDIATRIC USE
Maren Preis, Jens Broscheit, Norbert Roewer,
and Jörg Breitkreutz
Background: Midazolam is commonly used for
preoperative sedation of patients including
children. Midazolam has a bitter taste.
Therefore, tablets and solutions are often
rejected by the paediatric population.
Methods: Different concentrations of
midazolam hydrochloride and mixtures of
pure drug with cyclodextrins (α-, ß, γ- and
hydroxypropyl-ß-cyclodextrin), maltodextrins
and sweeteners were analyzed by two
different electronic taste sensing systems:
Formulating Better Medicines for Children
Insent® (Atsugi-Chi, Japan) and AlphaMOS
αAstree (Toulouse, France). Data obtained
from both systems were evaluated univariate
and by multivariate data analysis.
Findings: Insent® system was able to detect
pure midazolam hydrochloride in a linear
range from 0.01 mM to 10 mM. αAstree
detected only concentrations over 5 mM, so
the system was able to derect differences in
formulations but, could not differ low
concentrations of midazolam hydrochloride.
Drug:cyclodextrin mixtures showed reduced
sensor responses especially for bitterness
sensors (AN0 and BT0). Depending on the
type of cyclodextrin, taste information
obtained from Insent® revealed bitterness
reduction from 23.96 % to 35.84 % (BT0) and
from 38.42 % to 50.79 % (AN0). By adding
sweeteners an additional taste masking effect
could be detected, but not quantified due to
the underlying taste masking technique.
Conclusion: Taste masking of midazolam by
the help of different agents and detection of
their effects by electronic tongues, was
successfully performed. Cyclodextrins, in
particular ß-cyclodextrin, and maltodextrins
were able to reduce the free detectable
amount of midazolam hydrochloride, which
leads to the assumption that the drug has
been complexed by these agents.
45. A NEW BILASTINE TABLET:
DISPERSIBLE FOR PAEDIATRIC USE.
INDUSTRIAL SCALE-UP AND
STABILITY EVALUATION
E. Beascoa, L. González, C. Pumar , I. Ortega,
H. Blanco, K. Sustacha, E. Corta, A. Gonzalo,
M.L. Lucero
Faes Farma S.A., R & D and Innovation
Department, Av Autonomia 10, 48940 Leioa-
Bizkaia, SPAIN
email: [email protected]
A novel formulation was developed for
bilastine (Faes Farma S.A new H(1)-
antihistamine for allergic rhinoconjunctivitis
and urticaria treatment) providing an optimal,
feasible approach for paediatric population
(aged 4 and younger) under treatment.
Once special concerns for paediatric
population were reviewed, this easily-
produced 10mg teaspoon dispersible tablet
was industrially scaled-up. It was worth
mentioning that this formulation composition
included tolerable, safe excipients for children
without any warning or restriction(1)(2).
Scale-up of the implemented bilastine
formulation was performed from laboratory-
scale to pilot-scale batches (125,000 tablets)
at industrial facilities. Three equal-size
batches were manufactured in order to study
scale change at all manufacturing steps
presumed to be critical (such as lubrication
and hold- time and compression parameters).
Tablets with satisfactory organoleptic,
physico-mechanical and chemical properties
were obtained. Thus, feasibility of the
manufacturing process at this scale was
demonstrated.
Bilastine API stability was extensively studied
through development of Bilastine 20 mg
tablets (EMEA Approval: September 2010). On
the basis of a first-class API, stability for this
paediatric formulation was intended to be
well-supported.
A global stability design(3) was examined for
the three pilot-scale batches. Thermal,
pharmacotechnical, chemical and
microbiological tests met acceptance criteria
and showed no or little change trend over
time, even at accelerated conditions
(40ºC/75%RH 6 months). Critical appearance
and disintegrating properties did not present
any significant variation. Moreover, only
organic impurities derived from API synthesis
process were detected. Actually, no
degradation impurity was found. At present,
Formulating Better Medicines for Children
at least 2-year expiration period might be
proposed for registration application with
stability study data.
46. TASTE ASSESSMENT OF A FLAVORED
LOW PRICE LIQUID ORAL VEHICLE
FOR PEDIATRIC USE AMONG
CHILDREN AND PARENTS
Marina G. de Medeiros, Deborah S. Garruti,
Patrícia M. P. Thé, Maria Aparecida A. Josino,
Solange Cecilia C. Dantas, Said G. C. Fonseca,
Cristiani C.G.O. Lopes, Helena L. L. Coelho.
Research group Melhores Medicamentos para
Crianças (MeMeCri) - Federal University of
Ceará (UFC)- Fortaleza, Brasil)
Background: Lack of oral formulations
suitable for children led to the use of
extemporaneous formulations. Palatability is
a very important factors for pediatric
compliance. The study aims to determine
acceptability and preference of an oral liquid
vehicle under development in three flavors
among children and parents.
Methods: Flavors were cherry, mint and
strawberry, chosen based on preliminary
assessment at laboratory. Overall acceptance
hedonic tests were carried out using a hybrid
facial gender-specific seven-points hedonic
scale. Data were submitted to ANOVA,
Tukey's test (p < 0.05) and frequency
distribution. Ranking Preference was also
performed, with results analyzed by
Friedman's test. The study was approved by
ethic committee and written consent was
obtained from volunteers´ guardians.
Findings: 58 health children age from 4 to 12
and 21 parents participated. All samples were
well accepted by both children and parents,
with averages ranging between “liked” and
“loved” categories. Among children, all
samples showed more than 70% of responses
between "like" and "loved". There was
significant difference among samples being
mint the most accepted, with 88% of
responses in the acceptance region and 43%
only in "loved". There was no significant
difference in behavior between age groups.
Mint was the most preferred, but without
statistical significance. Among parents,
samples were equally accepted and preferred.
Discussion: Age had no effect on the
acceptability among children. Parents and
children accepted well all flavors. Children
preferred mint and parents showed no
preference. Further studies are needed to
assess the acceptability of extemporaneous
formulations prepared from the vehicle with
the medicine.
47. DEVELOPMENT OF A PEDIATRIC
FORMULATION FOR A POORLY
SOLUBLE ANTI-HIV COMPOUND
Roger Embrechts, Urbain Delaet, Guy Smans,
Albertina Arien*
*[email protected], PDMS Janssen Research
& Development, Janssen Pharmaceutica
Background & Objectives: The purpose of this
study was to develop an oral dosage form of a
poorly soluble compound for the treatment of
HIV in children from birth to the age of 18
years. The compound has a very poor
solubility in aqueous media. Therefore, three
formulation options, including a solution
employing a solvent, a suspension of the salt
form or a granulate for dispersion in food
were explored.
Methods: Three formulations of the anti-HIV
compound were developed and placed on
stability under different conditions to
evaluate physical and chemical stability. In
addition, the three formulations were
compared to a tablet formulation in a clinical
trial in adults.
Results and Discussion: The development of a
liquid formulation of the compound was
challenging. The hydrochloric salt was only
Formulating Better Medicines for Children
stable under very acidic conditions (pH <2.2)
and therefore it was a challenge to obtain a
stable suspension with stable pH, good
resuspendability and chemical stability upon
storage under various conditions .
Alternatively a solution containing PEG400
was developed. A number of antioxidants
were evaluated to prevent formaldehyde
formation at high temperatures. Third a
granulate was studied. The bioavailability of
these 3 formulations was compared to the
bioavailability of the tablet in a clinical study.
The results indicated that the suspension and
granulate had a good bioavailability. Based on
manufacturability, stability, and the intended
use of the formulation in the African setting,
the granulate formulation was selected for
further development into a pediatric
formulation.
48. EXPOSURE OF NEONATES TO TOXIC
PHARMACEUTICAL EXCIPIENTS IN AN
NICU IN BRASILIA, BRAZIL: A FOLLOW
UP STUDY.
Alcidésio S. Souza Jr, Sara C. C. Figueiredo,
Rafael S. Santos, Djanilson B. Santos, Helena L.
L. Coelho.
Research group Melhores Medicamentos para
Crianças (MeMeCri) - Federal University of
Ceará (UFC)- Fortaleza, Brasil)
The objective of this work was to identify
exposition to toxic excipients in neonates
hospitalized on a NICU at a public hospital in
Brasilia, Brazil during March 2010. The
inclusion criteria were neonates hospitalized
for more than 24 hours with prescription
drug; Patients were excluded if one or more
drug charts were missed. The prescriptions
were followed up daily; The risk assessment of
the excipients presented in the medicines was
investigated based on the Handbook of
Pharmaceutical Excipient 6th edn, 2009,
Pharmaceutical Press. During the study period
29 neonates were hospitalized, 21 atended
the inclusion criteria; The average gestational
age was 32 weeks (24 to 39 weeks); Most
patients were classified as preterm (n=12),
male (n=12) with diagnosis of prematurity and
respiratory distress. 40 drugs were prescribed,
the majority presented in a form of parenteral
drugs; The average number of prescriptions
per patient was 7,9, the median was 7 ranging
from 2 to 18 prescriptions (standard deviation
4,47). It was detected 12 excipients with
potential risk, including: Propylene Glycol,
Benzyl Alcohol, Sodium Metabisulfit, Lactose,
Lactic Acid, Sodium Benzoate, Benzalkonium
Chloride, Methylparaben, Propylparaben,
Sorbitol, Yellow Dye Tartrazine and
Polyethylene Glycol. The information about
the concentration of the excipients were
absent in the package leaflet. Preliminary data
shows that these neonates were exposed to
toxic excipients. The adverse consequences
and the possibility of to offer safer
alternatives, are being studied.
49. CHARACTERIZATION OF
COMMERCIALLY AVAILABLE ORAL
DISPERSIBLE FILMS (ODFS)
Ana Borges1,2([email protected]),
Cláudia Silva1, Jorge F. J. Coelho3, Sérgio
Simões1,2
[1]Bluepharma S.A.
[2]Faculty of Pharmacy, University of Coimbra
[3]CIEPQPF - Faculty of Science and
Technology, University of Coimbra
Background &Objective: ODFs have gained
increasing relevance as a new drug delivery
system due to its several advantages over
traditional dosage forms including the
administration to pediatric patients. The aim
of this study was to characterize commercially
available ODFs in order to provide essential
information for the definition of the target
product profile of our own ODF technology.
Formulating Better Medicines for Children
Methods: ODFs were evaluated in terms of
thickness, mechanical properties, residual
water content and dissolution time.
Results: The ODFs exhibit a very broad range
of thickness values [40-140μm], which is
probably associated with the height gap used
on the cast of ODFs production. The majority
of ODFs dissolved within 60 seconds [32-
105s]. FTIR analysis allowed the identification
of the main components (e.g. polymers and
plasticizers), while the interaction between
polymer molecules was difficult to investigate
due to the complexity of ODFs composition.
We also found a wide range of values for the
residual water content [2.91±0.17-9.75±0.53],
Young’s Modulus [51.23±5.33 -
1816.82±59.25Mpa], Breaking force
[1.51±0.09 - 35.46±7.31Mpa] and Elongation
properties [0.32±0.02 - 8.10±1.92%].
Conclusion: In general, we could not find a
correlation between the mechanical
properties and ODFs composition or the
residual water content. The complex
composition of the ODFs along with several
critical process parameters may explain the
significant differences on their characteristics.
Despite of these results, it was possible to
establish optimal ranges for the properties
under study that will be very useful for the
development of our own ODF technology.
50. FAST DISINTEGRATING TABLET
FORMULATION FORMING A VISCOUS
PULP EASY TO SWALLOW
S.Bold, P. Gruber
Losan Pharma GmbH, Neuenburg, Germany
Young children are mostly not able to swallow
tablets and capsules. Therefore often liquid or
jellylike preparations are applied to children
which are to be dosed and/or prepared by
parents. Therefore handling, dosability and
stability are often an issue for these
preparations.
A special tablet formulation was developed
that disintegrates in a pulp rapidly when
getting into contact with water (on a spoon or
in a syringe) and could be administered to
children easily.
Paracetamol granules were coated with
different coating formulations in order to
achieve taste masking and extended release,
respectively. The coated paracetamol
granules were than incorporated in a direct
compressible formulation based on highly
soluble and swellable components. The
formulations were optimized in order to
achieve a very fast disintegration of the
tablets within 30 seconds after adding a
maximum of 5 ml of water. A good taste
should be achieved by adding flavours and
sweeteners in combination with excipients
that cause a good mouthfeel. In addition taste
masking and extended release were tested for
the tablets, respectively.
We were able to formulate tablets that show
rapid disintegration on a spoon within 10
seconds. A viscous and good tasting pulp was
formed which was easy to swallow. Therefore
a single dosage form was developed that
allows an easy administration of medicine to
children without problems in dosability and
handling.
51. END-USER PERCEPTIONS,
PREFERENCES AND PRACTICES:
PILOTING THE ‘CHILDREN’S
ACCEPTABILITY OF ORAL
FORMULATIONS’ (CALF) MEDICINES
SURVEY
Sejal Ranmal, Anne Cram, and Catherine Tuleu
Background & Objectives: A lack of evidence
of end-user acceptability and attitudes to
dosage forms has been a longstanding
knowledge gap in paediatric formulation
development. The CALF project aims to survey
children and carers’ perceptions of solid oral
Formulating Better Medicines for Children
dosage forms, with the view to determine
suitability and paediatric-specific user
requirements. The objectives of this pilot
phase are to demonstrate the feasibility of
data collection instruments and validate
whether their findings correlate with actual
practices.
Methods: Age-adapted questionnaires were
used to survey a diverse population of
children aged 6-18 years, and where possible
their parents/carers. Following ethical
approval, data collection took place across 3
London hospitals and community settings
including pharmacies and schools. Item-
validation involved analysing whether
acceptable tablet and capsule size responses
on paper correlated with participants choices
when viewing (not ingesting) actual forms,
and where applicable, with the attributes of
their current medicines.
Results: To date, over 200 children and 150
carers have been surveyed, with data
collection ongoing. Preliminary analysis of
results shows strong preference for chewable
forms over orodispersibles or
multiparticulates/’sprinkles’ by children
across all age groups. Manipulation of dosage
forms was evident, with around one-fifth of
participants who had taken tablets 2 weeks
prior having crush or split them. Almost 80%
of young people aged 12 years and over found
10mm or larger tablets acceptable.
Conclusions: This study highlights the
importance of eliciting children’s unique
perspective relative to medicines use and
acceptability, to support industrial dosage
form design and clinical choice. The
questionnaires show promise for the next
stage of larger-scale data collection.
52. ACTIVELY INVOLVING CHILDREN AND
YOUNG PEOPLE IN RESEARCH –
LESSONS LEARNT FROM DEVELOPING
AND PRE-TESTING THE CALF SURVEY
QUESTIONNAIRES
Sejal Ranmal, Catherine Tuleu, and Jennifer
Newman
Background & Objective: Children’s rights are
in the spotlight, which has driven a focus
towards conducting research that
acknowledges them as autonomous and
competent social actors. Further, a national
UK strategy has highlighted the importance of
patient and public involvement in research
(PPI). This study involved actively engaging
with children and young people to aid in the
development of two age-adapted
questionnaires for the CALF (Children’s
Acceptability of Oral Formulations) Medicines
Survey.
Methods: Participants (n=39, aged 6-18years)
were members of the Medicines for Children
Research Network (MCRN) Young Person’s
Advisory Group (YPAG) and pupils at a London
NHS hospital school. The sample was diverse
with regards to backgrounds and experience
with medicines. Questionnaires were
reviewed and cognitively pre-tested using
think-aloud and probing techniques, to ensure
suitability in terms of comprehension,
usability and design. Further, qualitative
feedback was obtained through focus group
discussions.
Results: The questionnaires were revised and
study hypotheses developed based on
qualitative feedback. Interestingly, children
expressed concerns of the risk that coloured
medicines could be mistaken for
confectionary, reflecting in this being ranked
the least important formulation attribute.
Dosage form size was associated with efficacy,
with many perceiving that “bigger adult
medicines” would be “stronger” and “make
[them] better quicker”. While some favoured
mini-tablets, many children expressed
Formulating Better Medicines for Children
concerns that they could be difficult to
handle.
Conclusion: Children provided invaluable
feedback which aided the design and
development of the research. This study
highlights the importance and benefits of PPI,
and supports the paradigm shift to viewing
children as active participants, rather than
subjects of research.
53. 2ND GENERATION OF MINI-TABLET
DOSING DISPENSER - A SIMPLE AND
AFFORDABLE SOLUTION
Dr Rolf Eilers
[email protected], Balda Medical
GmbH & Co. KG, Germany
Mini-tablets are of interest as a dosage form
in the medicinal treatment of children as they
are,in principle, easy to dispense. However, if
a large number of mini-tablets, varying from
dose to dose, are to be dispensed simply and
reliably, a suitable tablet dispenser is
essential. An existing functional solution for a
mini-tablet dispenser1) uses appropriate
electronic means (motor and sensor
technology) to achieve accurate dosage. The
integrated electronics offer a high level of
flexibility as well as additional functions, but
this also involves increased development and
manufacturing costs. The objective was to
systematically develop an alternative, purely
mechanical, solution which would meet both
regulatory specifications and market
requirements. Following structured
brainstorming, a variety of designs were
selected on the basis of their technical
feasibility. These designs were then evaluated
with reference to regulatory specifications
and market requirements. Market
requirements were first studied within the
framework of market research. The designs
which then remained were converted into
functional models and subjected to thorough
testing.
The primary test criteria were dosage
accuracy, potential damage to the mini-
tablets caused by the system, and the
operative robustness of the system. As a
result, it was finally possible to refine a design
so that it met the basic specifications. The
design has been implemented in such a way
as to make it usable as a platform technology
for a variety of tablet shapes and sizes.
1) Micro Tablet Dosing Dispenser – Needs,
Challenges and First Solutions, Dr Rolf Eilers,
Oral Presentation at the 3rd EuPFI Conference
“Formulating Better Medicines for Children”,
Strasbourg, September 2011
54. DEVELOPING THE NEW TYPE OF ORAL
DOSAGE FORM FOR CHILDREN:
GT™(GEL TOGETHER)
Shuji Morimoto
The bitterness and smell of drugs is a big
obstacle for children taking medication. Most
of solid dosage forms are not preferred by
pre-school children [1].
GT is a pediatric oral dosage form which can
perfectly block bitter taste and bad smell. GT
is an elegant package containing drug and jelly
in separate compartments. The API is
wrapped in an edible thin film and
administered with jelly without taking water.
(Figures 1 and 2)
In this pilot study, the acceptability and
usability of GT for pre-school children (age of
2-6) was studied. 7 children participated with
support of their parents. 3 children aged 6
took placebo GT themselves, and another 4
participants (age 2-4) had GT administered by
their parents. 5 types of GT differing by size
and smell were administered to each child.
(Table 1)
The children preferred the strawberry taste of
jelly rather than lemon (68%vs 32%). 30
Formulating Better Medicines for Children
attempts taking GT were successful for
swallowing API without water. Type E was
most preferred for easy administration, and
80% of children would retake GT. Each type of
GT had 1 failure for reasons: afraid to take GT,
dislike jelly, hard to push jelly, API remained in
mouth after swallowing jelly.
GT has great potential for drug delivery to
pediatric patients.
55. TECHNOLOGY OF THE NEW TYPE OF
ORAL DOSAGE FORM FOR CHILDREN:
GEL TOGETHER (GT™)
Shuji Morimoto
Purpose: The newly-developed dosage form:
GT™ (Gel Together), which is an elegant
package containing a drug wrapped in an
edible film and viscous liquid (jelly) in
separate compartments was evaluated for
package design, in vitro dissolution, and filling
precision for pediatric use.
Method: For the package design, the pressure
of each sealing was measured, and ascorbic
acid was tested as a model drug for in vitro
dissolution. Filling precision was checked by
the automatic weight control.
Result: For the design, GT is divided into 3
parts by seals produced with different applied
pressure, heat and time levels. (Figure 1) The
pressure was 70kg maximum vertically, and
the package was easily operated by 2kg of
pinch power. The edible thin film
overwrapping the drug allowed rapid release
(Figure 2). Filling accuracy and precision was
measured by Automatic Weight Control:
accuracy was +/- 1.0 of target and precision
typically less than ±５％ CoV. Powder filling
was weighed on-line from 10mg to 1,500mg
and rejects were removed if they did not
meet acceptance criteria.
Conclusion: According to “EMEA reflection
paper 2006”, most solid dosage forms are not
preferred by pre-school children, and there
are few existing products containing jelly. In a
preliminary study, it was found that more
than 80% of pre-school children (age 2~6)
preferred GT for easy administration using
flavored jelly. GT has a great potential to
deliver drugs to pediatric patients.
56. AGE-APPROPRIATE EVALUATION
AND AVAILABILITY OF ENTERAL
DRUG FORMULATIONS
RECOMMENDED IN ESSENTIAL
MEDICINES LIST FOR CHILDREN
Jennifer C Duncan1*, Samuel Orubu2,
Catherine Tuleu2, Mark A Turner3, Anthony J
Nunn4
(1) Alder Hey Children's NHS Foundation
Trust, Liverpool, United Kingdom (2)
Department of Pharmaceutics & Centre for
Paediatric Pharmacy Research, UCL School of
Pharmacy, London, United Kingdom (3)
Liverpool Women’s NHS Foundation Trust,
Liverpool, United Kingdom. (4) Department of
Women's and Children's Health, University of
Liverpool, United Kingdom.
* Email: [email protected]
Background
Access to safe, effective but affordable
medicines and the need to formulate ‘better
medicines for children’ continues to be of
global concern1. In 2011, the 3rd edition of
the WHO Model List of Essential Medicines for
Formulating Better Medicines for Children
Children2 (EMLc) was published and guides
national access to medicines recommended
for use in children.
Our project aims to ensure that EMLc and
WHO Model Formulary (MF)
recommendations give access to age-
appropriate dosage forms available in major
world markets and to highlight drugs for
which no commercial, age-appropriate
formulation is available. This study was a pilot
to evaluate age-appropriateness of EMLc
antituberculosis medicines and their
commercial availability, within the UK.
Method
Consensus definitions of age-appropriate
dosage forms were agreed. Each formulation
listed in Section 6.2.4 (Antituberculosis
medicines) of EMLc was independently
examined by JCD and SO for age-
appropriateness of dose and age recorded in
MF. Disagreement was resolved by consensus
of AJN and CT. Commercially available
formulations were identified by searching
various resources including BNFc3,
Martindale4, Drugs.com5, Mims UK6 and
eMC7.
Findings
For 8 enteral drugs listed in Section 6.2.4,
there were 16 dosage forms and a total of 20
different products recommended. 6/20
products were considered “age-appropriate”
for all intended age-groups. 9/20 products
were commercially available in the UK;
however only 1/20 was both commercially
available and “age-appropriate”.
Discussion
Recommended dosage forms are not always
age-appropriate or available in major markets,
such as the UK. Systematic review of the
whole of EMLc will highlight drugs for which
age-appropriate formulations should be
developed and made commercially available.
References
1.Report of the 3rd Partners' Meeting on
Better Medicines for Children (November
2011). Accessed online at
http://www.who.int/childmedicines/progress
/Progress/en/index.html
2.WHO Model List of Essential Medicines for
CHILDREN - 3rd edition (March 2011).
Accessed online at
http://www.who.int/medicines/publications/
essentialmedicines/en/
3.British National Formulary for Children
(BNFc) 2011-2012. Accessed online at
http://www.medicinescomplete.com/mc/bnfc
/current/
4.Martindale – The Complete Drug Reference
(online version via Micromedex)
5.Drugs.com - Drug Information Online.
Accessed at http://www.drugs.com/
6.Mims UK Accessed online at
http://www.mims.co.uk/
7.Electronic Medicines Compendium (eMC).
Online at http://www.medicines.org.uk/emc/
8.European Medicines Agency (EMA).
Reflection paper: Formulations of choice for
the paediatric population. (2006) Available at:
http://www.ema.europa.eu/docs/en_GB/doc
ument_library/Scientific_guideline/2009/09/
WC500003782.pdf.
9.WHO 2011b. Development of paediatric
medicines: points to consider in
pharmaceutical development. Available at:
http://www.who.int/medicines/areas/quality
_safety/quality_assurance/Rev3-
PaediatricMedicinesDevelopment_QAS08-
257Rev3_17082011.pdf
10.European Medicines Agency (EMA) –
Paediatric Regulations (Dec 2006). Accessed
Online at
http://ec.europa.eu/health/files/eudralex/vol
-1/reg_2006_1901/reg_2006_1901_en.pdf
57. AMLODIPINE: EXPLORING THE
METHODS TO ACHIEVE A 2.5 MG
DOSE.
Formulating Better Medicines for Children
Paul J. McCague, James C. McElnay, Caoimhe
Quinn, Lesley-Ann McCullough, Ryan F.
Donnelly.
Clinical and Practice Group, School of
Pharmacy, Queen’s University Belfast.
Background: Amlodipine is used at a dose of
2.5 mg once daily for the treatment of
hypertension in children at all ages. Although
on the World Health Organisation Model List
of Essential Medicines for Children1,
amlodipine 2.5 mg tablets or oral liquid
formulation are not currently available as a
proprietary product in the United Kingdom.
Health care professionals, therefore, have to
either split 5 mg amlodipine tablets or
prepare an extemporaneous liquid
preparation to achieve the required dose. This
study aimed to determine the drug content of
extemporaneous preparations and compare
two methods to split a 5 mg amlodipine
tablet.
Methods: Ten community pharmacists were
recruited and each extemporaneously
prepared an amlodipine suspension and split
tablets using two routine methods: a
household kitchen knife and a commercially-
available “tablet splitter”. A validated HPLC
method was used to assess the drug content
of the extemporaneous preparations and the
‘split’ tablet segments were weighed.
Findings: The drug content of formulations
prepared by the pharmacists ranged from
84% to 138%. The mean drug content was
119% (±17.3, CI 95%). With regard to tablet
splitting, using a pill splitter gave a
significantly lower deviation from theoretical
weight (p<0.001) as well as a significantly
lower loss of dosage form through
fragmentation (p<0.001).
Discussion: The results show significant dose
deviations can occur while splitting tablets. A
large variation of drug content in
extemporaneous formulations was also
observed. Inaccurate dosing could have
serious clinical consequences in terms of sub-
therapeutic or toxic levels of drug being
absorbed. Availability of more licensed
products for paediatric use could potentially
have a positive impact on patient care and
may improve patient safety.
(1) World Health Organization (WHO), WHO
Model List of Essential Medicines for Children
– Second List, updated March 2010.
58. PAEDIATRIC EXTEMPORANEOUS
FORMULATIONS: A SERVICE
EVALUATION IN THE PRIMARY CARE
SETTING
Paul J. McCague, James C. McElnay, Ryan F.
Donnelly.
Clinical and Practice Research Group, School
of Pharmacy, Queen’s University Belfast
Background: For children who cannot take
adult dosage forms, a number of medicines
have to be prepared extemporaneously.
There has not been a published systematic
study to investigate the extent and type of
extemporaneous production of oral medicines
in community pharmacies in Northern Ireland
(NI). A service evaluation was therefore
conducted to investigate this.
Methods: A retrospective cross-sectional
population study was carried out in patients
<18 years from 1st April 2010-31st March
2011 who were being treated in primary care
in NI. Data were sought through the Business
Services Organisation and were extracted
from the Enhanced Prescribing Database,
which provides details of prescribed and
dispensed medications for each individual
registered with a general practitioner. Data
were analysed using SPSS 19.0.
Findings: Over the 12-month period, a total of
3,308 extemporaneously prepared
Formulating Better Medicines for Children
prescription items were dispensed to 548
individual patients <18 years old. Medicines
for disorders of the cardiovascular system
were the most common agents prepared- 767
preparations in total (23.2%). Other medicines
commonly prepared in this manner were for
disorders of the gastrointestinal system
(n=677, 20.5%), endocrine system (n=626,
18.9%) and central nervous system (n=609,
18.4%).
Discussion: The results show a considerable
number of extemporaneous preparations are
prepared in community pharmacies for
paediatric patients (123 different oral
formulations), particularly for disorders of the
cardiovascular system, gastro-intestinal tract,
endocrine system and central nervous system.
The results highlight the need for more
licensed products to be made available for use
in children and young people.
59. OPINIONS & EXPERIENCES OF
COMMUNITY AND HOSPITAL
PHARMACISTS ON
EXTEMPORANEOUS PREPARATION
OF MEDICINES AND SPECIALS.
Paul J. McCague, James C. McElnay, Ryan F.
Donnelly.
Clinical and Practice Research Group, School
of Pharmacy, Queen’s University Belfast
Background: Extemporaneous preparation of
medicines is one of the highest risk activities
carried out in pharmacies and often is
supported by a poor quality evidence base1.
Over the last few years, pharmacists in the UK
have increasingly used ‘specials’ rather than
making products extemporaneously2. This
study aimed to explore the experiences,
attitudes and beliefs held by dispensing
pharmacists in community and hospital
pharmacies.
Methods: After obtaining ethical approval, a
pre-piloted, self-administered online
questionnaire was emailed to all community
and hospital pharmacists (n=1706) registered
in Northern Ireland in April 2012. Two
reminders were distributed after four and six
weeks. Data were entered into SPSS 19.0 and
descriptive analysis used where appropriate.
Findings: Two hundred and ninety five
responses were received, providing a
response rate of 17.3%. The majority of
respondents were female (69%) and worked
in community pharmacy (74%). Over 80%
encountered at least one extemporaneous
formulation per week. Most pharmacists
(93%) were aware extemporaneous
formulations were unlicensed. However, only
12% of respondents believed prescribers were
aware of this. The majority of respondents
believed that ‘specials’ were of a better
quality (74%) and safer (70%) than
extemporaneous preparations.
Discussion: The findings to date suggest that
although pharmacists encounter
extemporaneous preparations on a weekly
basis they believe ‘specials’ are a better
quality product are safer for patients to use
than extemporaneously prepared products.
Further work will include a qualitative focus
group study to gain a deeper insight to the
issues which influence pharmacists’ beliefs on
the subject.
1. Gill AM, Leach HJ, Hughes J, Barker C,
Nunn AJ, Choonara I. Adverse drug reactions
in a paediatric intensive care unit. Acta
Paediatric 1995;84:438–41.
2. Royal Pharmaceutical Society,
http://www.rpharms.com/best-
practice/specials.asp Accessed 14 November
2011.
Formulating Better Medicines for Children
60. EXTEMPORANEOUS COMPOUNDING
IN NIGERIA – A PILOT STUDY OF A
CHILDREN’S UNIT IN A TERTIARY
HOSPITAL
Samuel Orubu1*, Chinyere Okwelogu2,
Olubisi Opanuga3, Tony Nunn4, Catherine
Tuleu1
1 UCL School of Pharmacy, London, UK 2
Faculty of Pharmacy, University of Lagos,
Nigeria 3 Lagos University
Teaching Hospital, Nigeria 4 University of
Liverpool, UK
*email: [email protected]
Background
Extemporaneous medicines are often
compounded for children in hospitals to
“supply” medicines that are not commercially
available1, 2. This practice has been well
documented, and analysed, for many
countries 1, 3-6 in efforts aimed at
improvements. Not much is known about the
compounding practices in Nigeria.
The aim of this work was to find out what
medicines are compounded in Nigeria, using
one tertiary hospital as a pilot study. The
objectives were to find out if these medicines
are available elsewhere in age-appropriate
formulations; and eventually to make
recommendations to policy makers as to how
access, or the practice, can be improved.
Methods
Medicines compounded from January to
December 2011 were extracted from records
at the children emergency pharmacy unit of
the University of Lagos Teaching Hospital.
Approval was obtained from the Ethics
committee before data collection.
Characteristics of medicines compounded –
strength, starting material, final dosage form;
and reasons for compounding, were noted.
Compendia were then checked for availability.
Findings
Products containing 29 active pharmaceutical
ingredients (APIs) were prepared in 793
compounding episodes. The five most-
frequently compounded APIs were Zinc
(264/793); Furosemide (224/793); Digoxin
(64/793); Rifampicin (62/793); and
Propranolol (54/793). All products were
suspensions. The main reason for
compounding was the unavailability of age-
appropriate dosage forms.
All of the most-frequently compounded
products were available as authorised, age-
appropriate medicines in other countries
(data in poster).
Discussion
This pilot study indicates that a range of
medicines are compounded in Nigeria. Most
of these are available as age-appropriate
formulations elsewhere.
References
1. Brion F, Nunn AJ, Rieutord A. 2003.
Extemporaneous (magistral) preparation of
oral medicines for children in European
hospitals. Acta Paediatr, 92 (4): 486 – 490.
2. Nahata MC, Allen LV Jr. 2008.
Extemporaneous drug formulations. Clin Ther,
30 (11):2112-2119.
3. Tuleu C, Marques J, Yeung V, Wong I.
2003. Extemporaneous manipulation of drugs
in a paediatric hospital pharmacy: an audit. Int
Journal of Pharm Pract; R78.
4. Yeung VW, Tuleu CLC, Wong ICK.
2004. National study of extemporaneous
preparations in English paediatric hospital
pharmacies. Paed Perinatal Drug Ther, 6 (2):
75 – 80.
5. Kairuz T et al. 2007. Extemporaneous
compounding in a sample of New Zealand
hospitals: a retrospective survey. New Zeal
Med J, 120 (1251): U2466.
6. Giam JA, McLachlan AJ. 2008.
Extemporaneous product use in paediatric
patients: a systematic review. Int J Pharm
Pract., 16: 3 – 10.
Formulating Better Medicines for Children
61. ORAL PRIORITY MEDICINES FOR
CHILDREN: AVAILABILITY IN THE
UNITED KINGDOM (U.K) AND UNITED
STATES (U.S)
Samuel Orubu1*, Jennifer Duncan2, Mark A
Turner3, Tony Nunn3, Catherine Tuleu1
1. UCL School of Pharmacy, London, UK. 2.
Alder Hey Children’s NHS Foundation Trust,
Liverpool, UK.
3. University of Liverpool, UK. * Email:
Background
The WHO has developed a list of life-saving
medicines for diseases of global health
importance in women and children below 51.
These medicines are meant to be available at
all public-health facilities. This is not always
the case, especially in developing countries 2.
The aim of this scoping study was to assess
how many medicines on the WHO list are
available by determining how many life-saving
oral medicines are licensed for children in the
UK and US.
Method
The electronic medicines compendium3 and
British National Formulary for Children4 (U.K);
and the National Library of Medicine’s
DailyMed5, and American Hospital-System
Formulary Service6 (U.S), were searched
online for oral priority medicines licensed for
children. Oral vaccines were excluded.
Findings
Of eight oral priority medicines, five were
available in U.K – Amoxicillin, Artemether-
Lumefantrine, Paracetamol, Morphine, and
Oral Rehydration Salts (as a country-specific
formula). 20mg Zinc, Vitamin A, and the
suggested fixed-dose combination anti-
retrovirals were not commercially available,
or licensed for use in children. In the U.S, only
Amoxicillin, Artemether-Lumefantrine, and
Paracetamol were available; Morphine was
not licensed for children.
Discussion
Formulations were licensed for 63% of oral
priority medicines for children in the U.K, and
38% in the U.S; indicating that these
medicines are not all licensed even in
developed countries. Licensing status is a
proxy for availability; and these results
suggest the situation is suboptimal. We
speculate that the world-wide availability of
these priority medicines depends on the
development of new formulations in at least
some cases.
References
1. WHO. 2012. Priority life-saving
medicines for women and children 2012.
Available online at:
http://www.who.int/medicines/publications/
EN_A4_WHOEMPMAR20121.pdf. [Last
accessed 25.05.12].
2. Robertson et al. 2008. What essential
medicines for children are on the shelf?
Available online at:
http://www.who.int/childmedicines/progress
/Robertsonetalpublished.pdf. [Last accessed
11.06.12]
3. Electronic medicines compendium.
http://www.medicines.org.uk/emc/ [Last
accessed 29.05.12]
4. BNF for Children 2011-2012.Available
at:
http://www.medicinescomplete.com/mc/bnfc
/current/
[Last accessed 11.06.12].
5. DailyMed.
http://dailymed.nlm.nih.gov/dailymed/ [Last
accessed 29.05.12]
6. AHFS. Available at:
http://www.ahfsdruginformation.com/ [Last
accessed 11.06.12]
Formulating Better Medicines for Children
62. MEDICINE FLAVOUR AND
FORMULATION PREFERENCE
AMONGST SCHOOL CHILDREN IN THE
WEST MIDLANDS REGION OF THE UK
Daniel Jon Kirby, Carly Tibbins, Claire Callens,
and John Marriott
This study aimed to determine the
preferences for flavour and formulation type
of medicines amongst school children in the
West Midlands region of the UK.
A total of 270 primary school aged children,
ages 3 – 11 from an inner city Birmingham
School participated in this pilot study. . The
surveys consisted of questions regarding
flavour and formulation type of medicines,
with preference being ranked with a
numerical scale. Surveys were completed
following an educational session delivered by
user involvement coordinators from the UK
Medicines for Children Research Network.
Within the sample population studied,
strawberry appeared to be the strong
preference for flavour, with cola and
chocolate also featuring frequently in the
responses. However, the flavours suggested
by the children were highly varied, suggesting
that a ‘one taste suits all’ approach would not
necessarily be successful.
In terms of formulation type, solid dosage
forms were the general preference for older
children (13 - 14 years old), whereas liquid
dosage forms were more preferable for the
younger age group (3 - 11 years old).
The results of this study highlight that,
although there is a general preference for
liquid dosage forms with a strawberry flavour,
this is far from universally accepted amongst
all age groups. In terms of flavour type, it
would be extremely difficult to produce a
formulation that pleased everyone, so
perhaps a complete masking of the taste of
the medicine – through microencapsulation
techniques, for example – may circumvent the
issue of palatability of medicines for children.
63. DIFFICULTIES IN ADMINISTERING
MEDICINES TO CHILDREN WITH
CHRONIC ILLNESSES AT HOME
Patrícia Q. da Costa, Marina G. de Medeiros,
Débora S. Gonçalves, Helena L. L. Coelho.
(Research group Melhores Medicamentos
para Crianças (MeMeCri)- Federal University
of Ceará (UFC)- Fortaleza, Brasil).
Background: Pediatric population faces many
issues in terms of medication. This work
aimed to identify difficulties and strategies
experienced by mothers to administer
medicines at home for their children with
chronic diseases.
Methods: Mothers and children were
identified at a pediatric hospital. Home
interviews 30-40 days after discharge
comprising socio-demographic data, clinical
history of the child, discharge prescription,
posterior prescription, difficulties of access
and administering each one of the medicines
and strategies to overcome child refusal.
Results: 28 interviews were completed.
Children mean age was 43,4 months (1 to
142), 16 female and 14 male.
Cardiorespiratory diseases were more
frequent, including asthma (14,3%),
congenital heart disease (14,3%) and cystic
fibrosis (10,7%). Main difficulties were lack of
at least one prescribed medicine at the public
health facility (26), no counseling about
medicine use at dispensing (30), bad taste of
medicines, including liquids (N=22, including
ferrous sulfate, metamizole drops, ranitidine
oral solution, acetaminophen drops,
phenobarbital drops) and solids (N=15; mainly
prednisone, captopril, spironolactone,
ranitidine, ethambutol), inappropriate dosage
Formulating Better Medicines for Children
form (15), including big tablets, tablets hard
to crush, hard to dissolve, residue of
suspensions, difficulty to apply aerosol, no
spacer to use antiasthmatics, inter alia.
Strategies: out of pocket purchase, crush
tablets, mix with water, juice, milk or other
foods, add sugar, administrate with syringe
inside the mouth profoundly to force children
or even missed doses and non-compliance.
Discussion: Lack of age appropriate
formulation leads to an additional struggle for
parents and children with chronic disease,
mainly at domicile, where some preparations
existent at hospitals are inexistent.
64. THE USE OF PILLGLIDE IN CHILDREN:
A PILOT STUDY
Mamta Jagani, Hélène Legay, Sejal Ranmal,
Kuan Ooi, and Catherine Tuleu
Background
Over 70% of medicines are tablets and
capsules and many children have difficulties
or are unable to swallow them. Liquid
medicines are the usual standard for children
but many have major palatability issues. The
purpose of the study is to investigate if a
swallowing aid (in the form of a flavoured
spray called PillGlide®) would help children
aged 3 years and above to take their solid or
liquid medicines compared to standard
behavioural approach alone.
Methods
Participants on multiple drug therapies
(unpalatable liquid, transitioning from liquid
to solid medicines) on HIV out-patients clinic
at GOSH were recruited. Participants used an
age appropriate diary to record ‘ease of
medicine taking’ with stickers adapted from
the 6 point validated Wong & Baker face scale
using the GOSH standard behavioural
intervention alone for two weeks and for the
third week, using the Pillglide® spray. Scores
for the 1st two weeks were compared against
the third week while using Pillglide.
Findings
Out of the 22 patients [6-17yo] enrolled in 9
months, 7 diaries were fully completed.
Sizes and shapes of solid dosage forms varied
(Table below).
Overall results were excellent for solid
medication for which Strawberry flavour was
preferred. Some very positive comments were
made by the kids. However for liquids, it did
not mask the taste or the after taste of the
medicine. (Figure above)
The pilot study is still ongoing. Further
recruitment results will be included in the
final poster.
If proven significantly helpful, Pillglide® should
be made available to children as it is safe and
easy to use.
References
(1) Diamond S, Lavallee DC. Experience with a
pill-swallowing enhancement aid. Clin Pediatr
(Phila). 2010;49:391-3.
(2) www.wongbakerfaces.org
65. PAEDIATRICIANS’ PERSPECTIVES AND
PRACTICES USING SOLID ORAL
DOSAGE FORMS FOR CHILDREN
Sejal Ranmal, Anne Cram, and Catherine Tuleu
Background & Objectives: Patient and end-
user acceptability should now be an integral
part of the evaluation of paediatric medicines
[1]. In addition, prescribers are also important
stakeholders who are likely to influence the
choice and use of paediatric medicines in
practice. As clinicians will prescribe based on
their views of what is deemed suitable, it is
valuable to gain insights into their attitudes
and habits. The objectives of this
opportunistic study were thus to elicit
paediatricians’ perceived suitability and
Formulating Better Medicines for Children
current or prospective practices using various
solid oral dosage forms.
Methods: A short self-completion
questionnaire was administered to delegates
at the Royal College of Paediatrics and Child
Health (RCPCH) 2012 Annual Conference
(n=95) in the UK. This convenience sample
consisted of prescribers from varying
backgrounds, specialities and levels of
experience/training in paediatrics, ranging
from foundation year doctors to consultants.
Results: In open question sections, numerous
respondents reported that they would consult
parents/carers, children themselves and even
nurses as to what they believe would be most
suitable. Most would generally start
prescribing monolithic dosage forms rather
than liquids from the age of 8-9 years (38%) or
10-11years (44%) for “medicines naïve”
patients or in acute settings. Multiparticulate
(“sprinkle”) forms were preferred most, while
34% would avoid mini-tablets; two
consultants reported they would fear the “risk
of inhalation” with these.
Discussion: Prescribers are important
stakeholders to consider in the use of
paediatric medicines, although a lack of
familiarity with dosage forms is evident. As
one consultant stated, “paediatricians need a
push towards prescribing non-liquid
medicines”.
References
[1] Committee for Medicinal Products for
Human Use (CHMP), Draft Guideline on
Pharmaceutical Development of Medicines for
Paediatric Use, EMA, May 2011
66. DRUG CHARACTERISTICS INFLUENCE
ON CHILDREN COMPLIANCE
Petkova Valentina1, Dimitrov Milen2*
1Department of Social Pharmacy, Faculty of
Pharmacy, Medical University, Sofia, Bulgaria
2Department of Pharmaceutical Technology
and Biopharmacy, Medical University, Sofia,
Bulgaria
Introduction: Drug medication for children
sometimes is very difficult. There are many
factors that influence it – bad taste,
unpleasant color or smell. Poor compliance
with therapeutic regimen has been observed
in all fields of treatment of children.
Objectives: The aim of this study is to test the
influence of the different characteristics of
the drug – taste, smell, color and shape on
children patient compliance and to develop an
effective guideline for the drug manufacturers
conformed to the specific preferences of the
Bulgarian children.
Design: A representative cross-section study
was performed. The applied methods were: -
open label, questionnaire survey with 50
children in Sofia, Bulgaria.
- development of different drug forms in 6
colors – yellow, pink, baby blue, red, green,
dark blue; in 8 tastes – strawberry, cherry,
orange, apple, peach, chocolate, banana,
apricot; in 4 specific forms – bear, fish,
elephant and heart). Experimental testing of
these formulations.
Setting: 10 GP practices and 10 community
pharmacies situated in the city of Sofia,
Bulgaria.
Participants: 50 patients aged 3-10 years with
their parents
Intervention: An initial interview with the
patients about the level of compliance, to
figure out the most often prescribed drugs
and to clarify the hinders for compliance.
Tasting of the above mentioned drug forms,
containing placebo.
Results and Conclusions: Inappropriate drug
form proves to be a hinder for children’
compliance (83%) – due to: unpleasant smell
(5%), bitterness(12%), unpleasant taste (29%),
unattractive drug forms (25%.. The results
Formulating Better Medicines for Children
from the experiment show difference
between the different drug forms tested. This
fact can explain the different flow rate of
patient’s health improvement. Bulgarian
children prefer the taste and smell of
strawberry and orange, pink and baby blue
colors, as well as the form of bears. These
results can intensified the production of drug
especially for the Bulgarian children, thus
granting good level of compliance.
Acknowledgement: This project No 18/2011 is
granted by the Medical Science council.
67. DEVELOPING NOVEL CERATES AS
SUBSTITUTES FOR WHITE SOFT
PARAFFIN
Joachim Köck
Background & Objectives
Due to new safety precautions for paediatric
patients [1], the use of White Soft Paraffin
(WSP) should be re-evaluated for
dermatological preparations. Traces of
aromatic molecules [2] and other potential
harmful substances have raised concerns in
paediatrics. Substances of natural origin like
cerates, defined as a mixture of waxes and
oils, are interesting candidates for
substitution of WSP.
Methods
Two batches of WSP were determined in
triplicates (WSP1, CaeLo and WSP2, Hansen &
Rosenthal). Cerates containing White Beeswax
(WB, CaeLo) and Medium-Chain Triglycerides
(MCT, Miglyol 812, Sasol) with varying WB
mass fractions from 15 to 25 % were chosen.
Stress controlled rheological measurements
were performed using a Kinexus Rotational
Rheometer (Malvern Instruments) with
settings shown in Table 1. Yield stress was
determined using a log-log plot of viscosity vs.
shear stress [3].
Table 1 Settings for determination of yield
stress
Findings
WSP1 features yield stress of 2.4 Pa ± 0.22 Pa
and WSP2 73.9 ± 27.4 Pa. The investigated
cerates show an exponential relationship
between WB mass fraction and yield stress.
Yield stress equivalent to WSP1 were not
found in the investigated cerates, whereas the
rheological properties of WSP2 can be
approximated with a composition of 17 % WB
and 83 % MCT.
Discussion
Rheological properties of WSP are highly
supplier- and batch-dependent and therefore
unpredictable, resulting in unreliable drug
preparations. In contrast, cerates can be
produced with predictable and adjustable
yield stress. For paediatric patients, cerates
are a very promising alternative and should be
further investigated for WSP substitution
including biopharmaceutical experiments
(drug release, penetration and permeation).
[1] Guideline on Pharmaceutical Development
of Medicines for Paediatric Use, in: CHMP
(Ed.) EMA/CHMP/QWP/180157/2011,
European Medicines Agency, London, 2011.
[2] U. Bogs, F. Hadj-Abo, Identification of
polycyclic aromatic substances in vaseline,
Zum Nachweis von polycyclischen Aromaten
in Vaselin., 25 (1970) 532-534.
[3] P.B. Laxton, J.C. Berg, Gel trapping of
dense colloids, Journal of Colloid and
Interface Science, 285 (2005) 152-157.
Stage Setting
Pre-shearing 100 s-1; 1 min
Resting period 10 min
Determination of yield
stress
1 Pa - 1000 Pa;
10 min